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2011 CMC Pisani
2011 CMC Pisani
Dipartimento Farmacochimico, Università degli Studi di Bari “Aldo Moro”, via Orabona, 4, I-70125, Bari, Italy
Abstract: The socioeconomic burden of multi-factorial pathologies, such as neurodegenerative diseases (NDs), is enormous worldwide.
Unfortunately, no proven disease-modifying therapy is available yet and in most cases (e.g., Alzheimer’s and Parkinson’s disease) the
approved drugs exert only palliative and symptomatic effects. Nowadays, an emerging strategy for the discovery of disease-modifying
drugs is based on the multi-target directed ligand (MTDL) design, an innovative shift from the traditional approach one-drug-one-target
to the more ambitious one-drug-more-targets goal. Herein, we review the discovery strategy, the mechanism of action and the bio-
pharmacological evaluation of multipotent ligands exhibiting monoamine oxidase (MAO) inhibition as the core activity with a potential
for the treatment of NDs. In particular, MAO inhibitors exhibiting additional acetylcholinesterase (AChE) or nitric oxide synthase (NOS)
inhibition, or ion chelation/antioxidant-radical scavenging/anti-inflammatory/A2A receptor antagonist/APP processing modulating
activities have been thoroughly examined.
Keywords: Multi-target directed ligands, Monoamine oxidase inhibition, Acetylcholinesterase inhibition, Neurodegenerative diseases,
Alzheimer’s disease, Parkinson’s disease.
MULTI-TARGET DIRECTED LIGANDS (MTDLs) within a unique formulation has been envisaged. Despite both
patient compliance and administration regimen may result
Largely spread pathologies such as neurodegenerative diseases improved, some disadvantages may arise from undesired drug-drug
(NDs), diabetes, cardiovascular diseases and cancer [1], share a interactions, extremely high variability of patient responses and an
common multi-factorial nature. They display complex and not fully unforeseeable toxicological profile. Within this frame, an emerging
understood onset and progression implying the deregulation of strategy is now coming to the attention of the medical and
multiple, and often unrelated, cellular physiological events that are pharmaceutical communities to improve the efficacy of the
caused by genetic, environmental and endogenous pathogenic therapeutic protocol and enhance the drug safety. This alternative
factors. The complexity of this biochemical landscape suggests that strategy is grounded on the assumption that a single, properly
the targeting of a single pathophysiological process among the array designed molecular entity, may be able to interfere with different
of the altered ones may be a challenging goal but it will likely result cellular events and cope with a multi-factorial disease more
largely inadequate to prevent, retard, halt or reverse the disease. efficiently [3]. The combination of different biochemical and
Over the years, deep efforts have been made in order to discover the pharmacological activities in a single molecule (multi-target
key biochemical events triggering these diseases and to identify the directed ligand, MTDL) [4] may provide a series of benefits mainly
most crucial druggable targets. Indeed, many new drugs showing a related to unique pharmacokinetic and pharmacodynamic patterns
single–target mechanism have been discovered and are currently in comparison to drugs cocktails. Indeed, the pharmacokinetic and
used in many multi-factorial pathologies although their therapeutic clinical profiling of a multipotent drug is greatly made easier, being
efficacy is limited to an essentially palliative and/or symptomatic limited to the study of ADME (adsorption, distribution, metabolism
effect. Hence, the discovery of genuine disease-modifying drugs and excretion) and toxicological properties of a single molecular
addressing a multi-factorial disease through a single-targeting entity. Moreover, the use of a multipotent drug will clearly simplify
action can be considered as a limited and generally losing strategy. the administration regimen, improve the patient compliance, and
The failure of the so-called one-drug-one-target paradigm avoid the risk of adverse drug-drug interactions.
urged researchers to investigate alternative ways to manage more Basically, the multiple action of a drug could be unveiled by
efficiently diseases triggered by the combination of several cellular serendipitous observations and by the repositioning study of old
aberrations and suggested a new and different approach by drugs, that is a systematic search of potential additional activities of
addressing simultaneously diverse biological targets that operate already-known molecules often revealing an unexpectedly wider
independently or cooperatively [2]. This approach might be applied pharmacological domain [5]. Next, the discovery of multipotent
by using a combination of two or more drugs (polypharmacology), molecules can be pursued through a knowledge-based or a library
each targeting a single biochemical process, or a single molecular screening approach [6]. In the former, the starting point is
entity able to exert beneficial therapeutic effects by modulating represented by a bioactive compound already biased towards a
different targets. specific target of interest. Typically, a series of rational structural
So far, the polypharmacology approach has represented the modifications are introduced to add further desired activities to the
most exploited way to tackle multi-factorial diseases and two main original one. The latter discovery method relies on the sequential
strategies have emerged in this field. As a first case, a cocktail of screenings of selected molecular libraries on the multiple targets of
two or more drugs addressing different biochemical targets have interest. These libraries are preliminarily screened to shortlist
been used following appropriate therapeutic protocols. The main compounds having the most desired/important biological activity.
problems associated with this approach reside in the low patient The filtered compounds are then subject to cross-screening towards
compliance and adherence, mostly due to the daily assumption of a other possible targets under investigation. Normally, the campaigns
high number of drugs often with repeated and varying doses, and in of wet screening are anticipated by a cheaper virtual screening
the high chance of drug-drug interactions and multiple competing performed by using as a query a multi-pharmacophore model
metabolic transformations. To overcome these drawbacks, a second integrating the common structural features shared by the
strategy that combines different drugs with a well defined dose ratio pharmacophore models developed for each single target.
When a more traditional, but very rational design strategy is
applied, the molecular framework of a multi-target molecule might
*Address correspondence to this author at the Dipartimento Farmacochimico,
Università degli Studi di Bari “Aldo Moro”, via Orabona, 4, I-70125, Bari, Italy; Tel:
be built up with three different approaches. One classical way
+390805442782; Fax: +390805442230; E-mail: carotti@farmchim.uniba.it consists in the molecular heterodimerization of two structurally
C F H
O U Y
N S B
J I R
U O I
G N D
A I
T Z
I A
O T
N I
O
N
LINKER
A B C
diverse scaffolds, each responsible for a different biological action. outer mitochondrial membrane to which is tightly bound through its
These molecules are structurally joined (conjugated) through an C-terminal sequence. This enzyme is ubiquitously distributed in
appropriate linker (compound A, Fig. 1), that can be either nature, both in human and animal tissues. Its biochemical function
metabolically stable or cleaved to release the two active moieties resides in the oxidative deamination of xenobiotic [8] and
(dual pro-drugs). endogenous amines, including monoamine neurotransmitters such
In a second method, the dual activity might be exhibited in the as serotonin (5-HT), noradrenaline (NA), and dopamine (DA) [9].
absence of a linker, by a compound resulting from the “exact Two distinct mechanisms have been postulated for MAO-A
fusion” (e.g., through a single bond connection) in a single degradation both leading to an iminium intermediate that is further
molecular entity of two molecules with different biological hydrolyzed to the final product, that is an aldehyde. As depicted in
activities (compound B, Fig. 1). A third strategy is based on the Fig. (2), one process is based on a single electron transfer (SET)
preliminary identification of the key structural fragments whereas the other involves a polar nucleophilic attack of the
(pharmacophoric features) responsible for a defined biochemical degradation-prone amine to the flavin cofactor (Fl, Fig. 2) [10].
activity in different molecules. Then these structural elements are Two distinct enzymatic isoforms, namely MAO-A and MAO-
combined in a novel unique, appropriately designed, molecular B, have been isolated and fully studied. They are characterized by
hybrid (compound C, Fig. 1) [7]. The latter is probably the most different amino acid sequences, three-dimensional structures [9],
exploited and feasible design method that can be applied when the organ and tissue distributions [11], sensitivity to inhibitors [12] and
two sets of “active” molecular fragments are easily identifiable and substrate specificity. Both enzymes oxidatively deaminate DA,
the structural similarity between the starting compounds is whereas MAO-A preferentially deaminates 5-HT, adrenaline and
relatively high. NA and is selectively inhibited by clorgyline. MAO-B
In most cases, the potential multi-target hit/lead compounds preferentially metabolizes benzylamine and -phenethylamine
coming out from all of these discovery strategies need further (PEA) and is inhibited by selegiline and rasagiline selectively.
optimization to suitably balance their in vitro and in vivo Isoform ratio and tissue distribution of MAOs may vary according
pharmacological properties. to the species. Thus human and rat liver express almost identical
levels of both MAO isoforms. MAO-A predominates in human
Monoamine Oxidases (MAOs): A “Druggable” Target in placenta and intestinal mucosa [13], whereas MAO-B is the
Neurodegenerative Diseases prevalent isoenzyme found in platelets [14]. Both isoforms are
present in rat and human brain, with proportions depending on the
Monoamine oxidase (MAO, EC 1.4.3.4, amine-oxygen specific neural region [15]. Adrenergic and histaminergic neurons
oxidoreductase) is a flavoenzyme localized at the inner side of the contain prevalently MAO-A and MAO-B isoforms, respectively.
4570 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
Flox Fl Fl Flred
-H H2O
R CH2 NH2 R CH2 NH2 R CH NH2 R CH NH2 R CHO
Taking into consideration the isoforms differences, the native role result, the clinical use of MAO-Is as antidepressants has been
of MAOs, and their consequent implication in the catabolic progressively reduced because they required severe dietary
degradation of many biogenic amine neurotransmitters, these restrictions and safer drugs such as tricyclic antidepressants and
enzymes have been regarded as attractive targets for the treatment selective serotonin reuptake inhibitors (SSRIs) have been preferred.
of widespread neurological disorders [16]. Several selective MAO- Currently, MAO-Is constitute the third- or fourth-line treatment of
A inhibitors exhibited antidepressant activity (e.g., moclobemide, depression [19].
brofaromine, clorgyline and toloxatone, Chart 1) [17]. whereas The inhibition of MAOs still represents an interesting field of
selective MAO-B inhibitors have been introduced in the therapy of research thanks to some new emerging and promising therapeutic
Parkinson’s disease [18] (PD) (e.g., lazabemide, selegiline, and perspectives. In fact, the ongoing medicinal chemistry research of
rasagiline, Chart 1). Iproniazid, originally used as an anti- selective and reversible MAO-A inhibitors (RIMA) with a better
tuberculosis agent, was the earliest unselective MAO inhibitor therapeutic profile, fewer drug-drug interaction, and lower adverse
introduced in the therapy of depressive disorders in the 1950s and effects is encouraged by solid evidence enlightening the
later withdrawn because of hepatotoxic side-effects. Other agents effectiveness of MAO-Is in the treatment of major depression,
acting as MAO inhibitors (MAO-Is) that still exhibited a non- treatment-resistant major depressive disorder and bipolar
selective inhibition of both isoenzymes (phenelzine, isocarboxazid, depression [19]. Moreover, MAO-B inhibitors gained also new
and tranylcypromine, Chart 1) have been later introduced. The consensus as safer drugs for the treatment of early-phase PD,
major drawbacks linked to these antidepressants were represented providing symptomatic relief of motor deficits and retarding the
by severe side-effects such as the hepatotoxicity and the need of levodopa administration. Interestingly, they exhibited a
hypertensive crisis triggered by the consumption of tyramine-rich wide tolerability and may perform a disease-modifying action in the
food (e.g., wine, beer and especially cheese and therefore called long-term treatment of PD [20].
“cheese-effect”). Since 80% of intestinal MAOs is constituted by
the A isoform, the block of this enzyme is responsible for the halted In addition, a very recent and renewed interest has regarded
degradation of tyramine and the “cheese effect” can be therefore MAOs as potential targets in other NDs such as Alzheimer’s and
ascribed to the lack of selectivity of the earliest MAO-Is. As a Huntington’s disease (AD and HD, respectively), and amyotrophic
O
H
H H O N
N N N NH2
NH2 N N H
H N
O
N O O N
N
O N
H
O
Cl Cl
O
Br
Brofaromine (A) Moclobemide (A) Toloxatone (A) Clorgyline (A)
O HN
NH2 N
N
H
N
Cl
Lazabemide (B) Selegiline (B) Rasagiline (B)
Chart 1. Chemical structures of non-selective (NS) and selective MAO-A (A) and MAO-B (B) inhibitors.
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4571
lateral sclerosis (ALS). Within the complex biochemical portrait stress conditions [22], biometals imbalance [23], protein misfolding
compromising neuronal viability in these pathologies, some cellular and aggregation [24], and mitochondrial damage [25] play a crucial
impairments may be ascribed to the enzymatic activity and peculiar role.
mechanism of action of MAO. The enzymatic action of MAOs sets The scope of the present review is the collection and discussion
the reduction of neurotransmitter levels in the synaptic cleft, thus of the main results of the research projects focused on the discovery
altering the signalling transfer mechanisms. Moreover, as a result of of multipotent ligands showing MAO inhibitory activity as a key
the oxidative deamination of neurotransmitters and xenobiotic biochemical feature. Since MAO inhibition occupies a central role
amines, hydrogen peroxide (H2O2) is produced. H2O2 represents a in neurodegeneration, we paid attention to multi-target molecules
strong oxidant itself and is a precursor of radical reactive oxygen with a therapeutic potential for AD, PD, HD and ALS. From a
species (ROS), that can promote harmful cellular alterations in literature survey, in contrast with other targets (e.g., AChE) MAO
pathological conditions. Hydrogen peroxide generated through inhibition via multi-target ligands has not extensively attracted the
MAO catalytic cycle can interact with free Fe2+ cation in the Fenton attention of medicinal chemists although convincing experimental
reaction (Scheme 1), resulting in the production of ROS and evidence demonstrated the pivotal role of these enzymes in NDs.
neuronal oxidative stress. Therefore, MAO activity is thought to To date, MTDL strategy targeting MAOs among other targets
play a key role to the onset of oxidative stress. In physiological represents an elegant and promising strategy even if it has not led
conditions, ROS, e.g., superoxide radical anion (·O2-), hydroxyl yet to novel clinical therapeutics, with the exception of rasagiline
radical (·OH), and hydrogen peroxide are produced through several whose multi-targeting profile has been discovered later.
processes including mitochondrial respiration, cellular metabolism, Interestingly, some drug candidates emerged from MTDL design
and degradation of dietary components. Cellular ROS levels are showed promising multi-target properties and have been submitted
balanced by the action of an endogenous detoxification system to extensive bio-pharmacological profiling, as described in the
involving glutathione (GSH) and several enzymes, namely present survey.
glutathione reductase (GRD) and glutathione peroxidase (GPX),
catalase (CAT) and superoxide dismutase (SOD). These redox
systems are responsible for the transformation of these reactive Rasagiline as a Multipotent MAO Inhibitor
species in non-toxic compounds. When the amount of ROS is Rasagiline (1) (N-propargyl-1-(R)-(+)-aminoindan) [26], the R-
extensively increased and/or the efficacy of this protective redox isomer of a molecule originally coded as AGN1135, is a potent,
system is impaired in many pathological conditions, ROS highly selective and irreversible MAO-B inhibitor which has been
production becomes potentially harmful. Oxidative radicals may developed as an anti-Parkinson drug in monotherapy or as an
react with proteins and DNA, producing base-pair mutations, adjuvant drug in levodopa treatment [27]. In comparison to
deletions and insertions [21], and cause lipid peroxidation, thus selegiline (2), that is another potent, selective and irreversible
affecting cell membrane integrity. Ultimately, these biochemical “suicide-type” MAO-B inhibitor, the pharmacokinetic profile of
aberrations induced by ROS lead to cellular damage and death. rasagiline presents safer features since it is not linked to the in vivo
MAO metabolic production of L-amphetamine and L-methamphetamine
oxidation [28] responsible for some sympathomimetic adverse effects such as
increased blood pressure and heart rate [29]. In addition, rasagiline
dopamine shows a neuroprotective and anti-apoptotic action in PC-12 and
biosynthesis neuroblastoma SH-SY5Y cellular lines against different
Fe 2+ -OH neurotoxins such as SIN-1 (a peroxynitrite donor) [30], MPTP [31],
Fe 2+ 6-hydroxydopamine (6-OHDA) [32], and N-methyl-(R)-salsolinol
Fenion reaction [33] and protects from neuronal damage caused by several insults in
vivo, e.g., global ischemia, anoxia and head injury [34].
dopamine H2O2
autoxidation
GSH GRD
SOD N
GSSG
GPX
HN
CAT
-O2+ H2O
Rasagiline (1) Selegiline (2)
respiration
O2 rat brain: rat brain:
MAO-A IC50 = 412 nM MAO-A IC50 = 944 nM
Scheme 1. ROS endogenous production and detoxification system. MAO-B IC50 = 4.43 nM MAO-B IC50 = 3.63 nM
For all these reasons, MAO may be considered one of the most
interesting potential target in the design of multipotent ligands that human: human:
might exhibit a disease-modifying activity towards multi-factorial MAO-A IC50 = 710 nM MAO-A IC50 = 1700 nM
NDs. MAO-B IC50 = 14.0 nM MAO-B IC50 = 6.80 nM
The extension of life expectancy along with the progressive Fig. (3). MAOs inhibitory activities of rasagiline (1) and selegiline (2) [35].
increase of elderly population and improvements of health care
Strong evidence supports the idea that this neuroprotection is
claim for a great attention towards age-related NDs (e.g. AD, PD,
not related to the inhibition of MAO enzymatic activity. As a matter
HD and ALS). Each pathology possesses its characteristic
of fact, the S-isomer of rasagiline, called TVP1022, differs from
symptomatic manifestations, histological hallmarks and
rasagiline being a 2000-fold weaker human MAO-B inhibitor (IC50
biochemical mechanisms. Nevertheless, NDs share some common
equal to 28.7 versus 0.014 μM) [35] but holds comparable
and general impairments ultimately leading to neuronal death
neuroprotective activity. Therefore, this action has been ascribed to
and/or loss of neuronal functionality. Among others, oxidative
4572 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
the presence of the reactive propargylamino moiety which might plaques), soluble peptidic fragments mainly located in neocortical
interfere with many other cellular processes [36]. It has been regions and derived from sequential - and -secretase proteolytic
demonstrated that rasagiline acts on different key steps of the cleavage of APP; and ii) intracellular neurofibrillary tangles (NFT),
apoptotic cascade. In fact, 1 up-regulates the expression of paired helical structures mainly constituted of insoluble
antiapoptotic proteins Bcl-2 and Bcl-xl, belonging to Bcl-2 family, hyperphosphorylated protein, accumulated in the medial temporal
while down-regulates Bad and Bax [37], through the stimulation of lobe [44]. These biochemical hallmarks are associated with an
PKC and and inhibition of pro-apoptotic PKC and . Moreover, increased oxidative stress, abnormalities in endoplasmic reticulum
rasagiline prevents the decline in mitochondrial membrane and deficiencies in the clearance process operated by the ubiquitine-
potential, the activation of caspase 3, and the nuclear translocation proteasome system (UPS). Both A oligomers and self-aggregates
of glyceraldehyde-3-phosphate dehydrogenase [38]. The are cytotoxic so that oxidative and inflammatory insults seem to be
consequence is the block of both the mitochondrial swelling a direct consequence of the misfolding of these proteins in neuronal
process and the opening of the permeability transition pore, that are cells. AD is characterized by the progressive loss of brain capacities
two cellular events that initiate the apoptotic cascade. Interestingly, including memory loss, learning and language difficulties, and
rasagiline and some related propargylamines, promote the non- diminished simple problem-solving capabilities mainly controlled
amyloidogenic processing of amyloid precursor protein (APP) by by the cholinergic neurotransmission. In basal forebrain cholinergic
stimulating the PKC and MAP-kinase mediated cleavage operated neurons of late-stage AD patients, it has been documented a
by -secretase [37c, 39]. This proteolytic pathway produces soluble dramatically reduced level of neurotrophins, that manage learning,
fragments of APP (sAPP) that are unable to initiate the amyloid memory and behaviour in physiological conditions [44]. On this
cascade leading to the neurotoxic fibrillogenesis [40]. ground, the so-called “cholinergic hypothesis” has been proposed
Furthermore, ADME studies of rasagiline highlighted the role [45] which suggested the enhancement of the acetylcholine (ACh)
of its major hepatic metabolite, the 1-(R)-aminoindan, which is still concentration and/or of its action in the CNS, as a viable and
a weak and reversible MAO inhibitor endowed with winning strategy to solve cognitive and behavioural symptoms. In
neuroprotective properties that could contribute to the overall principle, this goal may be attained throughout the use of AChE-Is
biological effects observed for rasagiline [41]. [46] or sub-type selective muscarinic agonists [47].
Taken together, these findings lead to the conclusion that An increased potential efficacy of some AChE-Is stems from
rasagiline could be considered a highly valuable drug against PD the occasional discovery of a non-catalytic action of the enzyme,
not only for a symptomatic dopamine-replacement therapy but also whose peripheral anionic subsite (PAS) proved to be the structural
for a promising disease-modifying profile of the severe motor and motif involved in the promotion of the aggregation of A to form
neurological deficiencies of PD [27a, 42]. the amyloid plaques [48].
Nowadays, inhibition of AChE represents the predominant
Dual MAO-Acetylcholinesterase (AChE) Inhibitors pharmacological approach that has led to the development of anti-
Alzheimer drugs. Three AChE-Is (Chart 2), i.e., donepezil,
Alzheimer’s disease (AD) is the most diffuse form of senile rivastigmine and galantamine – the hepatotoxic tacrine was
dementia and represents the fourth leading cause of death in withdrawn from the market – are currently used in clinical practice
western countries. More than one century has passed from the in the moderate form of AD but their therapeutic efficacy is still
discovery of this disease by the German neuropsychiatrist Alois under debate, since they act symptomatically in relieving the AD-
Alzheimer [43] and different studies have been undertaken to shed related cognitive decline by restoring adequate levels of ACh
light into the pathophysiological mechanisms underlying this without affecting the leading causes of cholinergic neuronal loss
devastating neurological disorder. Notwithstanding, a complete [49]. Another drug, memantine, with a different mechanism of
comprehension of the origin and progression of AD is far to be action (NMDA antagonism) and a limited efficacy is now available
reached. What is clear is the fact that AD is a complex disease to treat AD in a more advanced stage.
triggered by several cellular impairments regarding, among many
others, cholinergic neurons deficit in the basal forebrain ultimately Behind the central role of cholinergic transmission, the
leading to neuronal loss. From a histopathological viewpoint, complexity of AD advocated many other triggering factors of the
convincing studies identified some unequivocal hallmarks of AD: i) neurodegenerative process. One of them is the “amyloid cascade”,
extracellular fibrillary aggregates of -amyloid (A) peptide (senile whose study has led to a deeper comprehension of the pathology of
N
O N
N
O
NH2
NH2
Tacrine (Cognex®) Rivastigmine (Exelon®) Memantine (Namenda®)
OH
O N
O
O
O
N
O
Galantamine (Reminyl®) Donepezil (Aricept®)
R2
R1
N N R4
R3
(3a)
R1 = R2 = H;
R3 = R4 = Me
AChE n.d.
MAO-A IC50 = 0.92 μM
MAO-B IC50 = 317 μM
R1 R2
O
N N R4
R3
(3b) (3c) (3d) (3e)
R1 = NHMe; R2 = H R1 = NHMe; R2 = H; R1 = NHMe; R2 = Br; R1 = NMe2; R2 = Br;
R3 = R4 = Me R3 = Me; R4 = Et R3 = Me; R4 = Et R3 = R4 = Me
AChE IC50 = 3.36 μM AChE IC50 = 5.68 μM AChE IC50 = 0.14 μM AChE IC50 = 0.060 μM
MAO-A IC50 = 13.6 μM MAO-A IC50 = 3.74 μM MAO-A IC50 = 0.21 μM MAO-A IC50 = 0.54 μM
MAO-B IC50 = >1000 μM MAO-B IC50 = >1000 μM MAO-B IC50 = >1000 μM MAO-B IC50 = 51.0 μM
Fig. (4). Tricyclic derivatives 3 with dual MAO-AChE inhibitory activity [59].
AD and has provided insights for the design of new potential biological actions. Hopefully, the resulting hybrid molecules will
therapeutic agents [50]. According to this hypothesis, the increase retain the biological activities associated to each different
of A production and the aggregation into low-molecular weight pharmacophore and exert beneficial effects from the synergy of
oligomers, protofibrils, fibrils and ultimately amyloid plaques, are these combined mechanisms.
the leading causes of the onset and progression of AD. The A pioneering work in the field of hybrid multi-target anti-AD
reduction of both A formation (with - and -secretases drugs was carried out by D. M. Fink and M. G. Palermo [59]. They
modulators) [51, 52] and aggregation (with anti-aggregating agents)
designed dual MAO-AChE inhibitors by decorating a tricyclic
[53], and the increase of the A clearance (with active and passive 1,2,3,4-tetrahydrocyclopent[b]indole carbamate scaffold, inspired
immunization [54]) are potential therapeutic strategies for the by the known AChE-I physostigmine, with a propargylamino
therapy of AD. Recent studies enlightened also the role of oxidative group, a recurrent pharmacophoric group of different MAO-Is.
stress [55], metal ion dyshomeostasis, and inflammation in AD
pathogenesis. Neuronal death is the result of different insults, The interest for this molecular series might be limited by their
comprising bio-macromolecules alteration upon peroxidation irreversible and selective MAO-A inhibition due to the presence of
reactions. Oxidative damage may arise from MAO-induced free the reactive N-propargylamino group, that is likely associated to
radicals, mitochondrial abnormalities, inflammation, or redox active adverse side-effects [60]. More interestingly, the synthetic iminic
metals, that can contribute to the excessive production of toxic ROS intermediates (3a-3e) were also tested and showed from moderate
through Fenton chemistry. (3b-3c) to good (3d-3e) dual inhibitory activities. Regarding MAO
inhibition, 3b-3e exhibited a reversible mechanism of action and a
Within this complex scenario, MAO-Is might play a beneficial marked selectivity for MAO-A. Thus structure-affinity and
neuroprotective action in NDs by reducing oxidative stress structure-selectivity relationships, SARs and SSRs, respectively,
conditions [27d, 56]. The following experimental evidences support
were examined for these derivatives. The introduction of the
this research line: i) up to 3-fold increased MAO-B activity in the
carbamate moiety induced a weak affinity for AChE while reducing
temporal, parietal and frontal cortex has been observed in patients MAO-A inhibition not so drastically (compare 3a and 3b, Fig. 4). A
suffering from AD compared to control healthy patients [57]; ii) the critical influence was exerted by the R4 substituent at the iminic
connection between behavioural disorders and the observed
nitrogen. Increasing the size of R4 alkyl groups had a slighter
modification in other neurotransmitter systems is mediated by
influence over AChE than over MAO inhibitory potency (compare
biogenic amines (e.g., serotonin, noradrenaline) whose level is 3b and 3c), the ethyl group being the best substituent to maintain a
influenced by the catabolic action of MAOs.
good dual activity as proved by derivative 3c. The R2 substituent
The high complexity of AD calls for a huge effort to find ortho to the carbamate moiety affected both enzymatic activities
molecules able to modulate multiple CNS targets and then to leading to the very interesting compounds 3d-3e. Unfortunately, a
promote a real improvement of AD therapy. The multi-factorial further development of these compounds was halted by the low oral
nature of the disease rules out the use of consolidated mono-therapy activity and poor brain penetration found during ex vivo studies on
and put researchers on the way of multipotent drugs hitting brain tissues.
cooperatively different targets underlying the onset and/or Starting from the observation that ensaculin, a compound
progression of the disease. This approach is grounded on the idea
bearing a coumarin skeleton, showed an interesting AChE
that an AChE-I could exhibit a more efficient therapeutic effect in inhibition in vitro (IC50 = 0.36 μM) [61], a set of various 7-
AD when able to express an additional MAO inhibitory activity, substituted coumarin derivatives (Fig. 5), previously synthesized
limiting the sources of ROS-related neurotoxicity [58].
and characterized as potent MAO inhibitors [62], was screened by
As already mentioned, one of the most exploited way to obtain some of us on AChE. All the tested derivatives inhibited AChE
a MTDL is to combine in a unique molecular framework different with Ki values in the medium to low micromolar range (3-100 μM)
pharmacophoric features responsible for well-defined and different [63]. As for MAO inhibition, they were endowed with micromolar
4574 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
N R1
O N O
R2
O O O
O O O
Ensaculin (4a-g)
Fig. (5). Ensaculin and coumarin derivatives 4 with dual MAO-AChE inhibitory activity.
Table 1. MAO and AChE Inhibition Data of Coumarin Derivatives 4a-g [62]
to low nanomolar affinities and a marked selectivity for the B affinity and selectivity over MAO-A. Compound 4g would deserve
isoenzyme. The benzyloxy group linked to C7 of coumarin ring was further optimization and investigation as a potential anti-Alzheimer
the main molecular determinant of the high MAO-B affinity and its agent.
absence reduced, albeit less drastically, the AChE inhibition (see Youdim and coll. studied a very large series of N-
compound 4a in Table 1). To ascertain the mechanism of AChE propargylaminoindans and N-propargyl-phenethylamines (Fig. 6) as
inhibition by compounds 4, a kinetic analysis of selected 7- dual MAO-AChE inhibitors [65]. The molecular design was based
benzyloxy coumarins was undertaken. Lineweaver-Burk and Hanes on the combination in the same molecule of a propargylaminic
plots highlighted the non-competitive character of the AChE
fragment, characterising well known MAO-Is such as rasagiline and
inhibition, that could be of great interest in the context of selegiline, with a carbamate moiety, which could add the AChE
Alzheimer’s disease as this kinetic mechanism may be ascribed to
inhibitory property. In addition to AChE and MAO-B inhibition
the interaction of the inhibitor at the PAS. This kinetic behaviour
these molecules might display a potential antidepressant action,
was later confirmed on a series of potent and selective
through MAO-A inhibition, and induce a neuroprotective effect
heterodimeric AChE-Is containing the coumarin ring [64]. The
unrelated to MAO inhibition, due to the presence of the
coumarin nucleus resulted optimal for the dual AChE-MAO affinity
propargylamino group. MAO-A inhibition showed by derivatives 5-
and its replacement with a 4H-chromen-4-one reduced both
6 constitutes only an apparent drawback linked to possible
enzymatic inhibitory potencies. The introduction of an additional
tyramine-potentiation because a stronger and more specific
methyl group at position 3 of the coumarin ring increased both
inhibition of central with respect to the peripheral (liver and
MAO and AChE affinity (compare 4b and 4c in Table 1). Focused
intestine) MAO-A was claimed [66]. In this research project, two
SARs on the benzyloxy substitution pattern revealed that
substituents in meta position decreased the AChE affinity hit compounds belonging to the indan family (5a-b) have been
(compounds 4d-4f) with the notable exception of the m-chloro identified along with an additional candidate bearing a
substituent (compound 4g), that resulted the most potent AChE phenethylamine system (6). Ladostigil (5b, TV3326) has
inhibitor of the whole series and exhibited outstanding MAO-B comparable equine butyrylcholinesterase (BChE) and human AChE
R4
O R3 R1
R3 N O N
N O R4
R2 N O R2
R1
(5a) Ladostigil (5b) (6)
R1 = H; R2 = Me; R1 = H; R2 = Me; R1 = R2 = R3 = Me;
R3 = n-Pr; R4 = Cl R3 = Et; R4 = H R4 = n-Hexyl
Fig. (6). Carbamate derivatives 5-6 with dual MAO-AChE inhibition activity [65].
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4575
inhibitory activity, with a greater potency against the former and a mechanism of action. Interestingly, these N-substituted pyrazolines
duration of action longer than rivastigmine. At a preliminary stage, were also active against human erythrocyte and plasma AChE and
the introduction of the carbamate moiety resulted in the loss of exhibited a selective, reversible and non-competitive inhibition
MAO inhibitory activity, as assessed by in vitro assays on rat brain profile. The comparison of compounds 7a and 7b shows that AChE
homogenates. Notwithstanding, ladostigil, submitted to in vivo affinity was notably decreased by the increasing size of the R 1
studies showed a dose-dependent and not selective MAO-A/-B substituent of the thiocarbamoyl exocyclic nitrogen. The optimal
inhibition in rats, mice and monkeys after chronic oral substitution of the phenyl ring and the thioureidic moiety,
administration (25–150 mmol/kg dose once daily, for 14 days) [67]. represented by a p-methoxy and a methyl group, respectively,
Fortunately, MAO-A inhibition activity was markedly less furnished a promising derivative (7a) exhibiting a strong AChE
pronounced in liver and small intestine than in CNS and this result affinity with an IC50 in the nanomolar range and a moderate MAO-
was attributed to the action of local active metabolites in the CNS. B inhibitory potency and selectivity.
The 6-hydroxy derivative, produced by the metabolic degradation Despite the outstanding innovations in synthetic organic
of the carbamic group, has weak in vitro activities (IC50 against chemistry that could have expedited the preparation of new
MAO-A and B of 0.46 mM and 0.35 mM, respectively). Thanks to bioactive compounds, nature still remains a great source of
these central effects, ladostigil is able to elevate dopamine, structurally diverse and promising molecules for the drug discovery
noradrenaline and serotonin levels and these synergic actions result process. To perform a medium/high-throughput screening of
in a promising antidepressant profile. Moreover, by lacking naturally-derived products, an efficient microtitre plate method
peripheral activity on both MAO isoforms, this molecule is devoid based on Ellman’s assay was developed and validated for the study
of the cardiovascular side-effects associated with tyramine-induced of both electric eel AChE inhibition and kinetic behaviour [74].
“cheese-effect”. Ladostigil prevents MPTP-induced parkinsonism When this microplate technique was applied to the biological
in mice model [68], as a typical MAO-B inhibitor, and shows screening of a library of 45 non-alkaloidal natural compounds in the
neuroprotective functions similar to those of rasagiline in several in search of novel AChE-Is, several xanthones were identified as good
vitro [69] and in vivo models [70], likely due to the presence of the to moderate inhibitors. Four of them (8a-c and 9, Fig. 8) are worth
propargylaminic moiety. As demonstrated for the well-known noting because previous studies had highlighted their promising
propargylaminic MAO-Is selegiline and rasagiline, additional MAO affinity [74b], thus representing dual AChE-MAO ligands.
neuroprotective mechanisms might be exerted through the block of Electron-absorption spectroscopy revealed that the mechanism of
cellular death signalling process and the production of different these reversible MAO-Is is likely mediated by the formation of
neurotrophic factors, namely neurotrophins and ligands of glial cell charge-transfer complexes with FAD cofactor. Actually, these
line-derived neurotrophic factor [71]. Further investigations for xanthones showed interesting inhibitory activities towards AChE
these novel classes of multipotent molecules are warranted to meet and MAO, albeit no pronounced MAO isoform selectivity was
the following goals: (a) closer AChE and MAO-B affinities, (b) observed with the exception of 8a and 8b that were considerably
good to moderate AChE inhibition and (c) improved MAO-B more active towards the A isoform. In the kinetic analysis,
affinity and MAO-B over MAO-A selectivity. xanthones 8a-c behave as mixed-type inhibitors of AChE and
R2 compound 9 shows a non-competitive profile. These data suggested
a partial binding at PAS, and a possible consequent inhibition of -
amyloid formation induced by AChE.
R1
R6 O OH
O OH
R5 R2
R4 O R3
O OH
R1 = R4 = OH; R1 = R6 = OMe; R1 = R5 = H;
R2 = R3 = R5 = H; R2 = R3 = R5 = H; R2 = R3 = R6 = OMe;
R6 = OMe R4 = OH R4 = OH
AChE Ki = 53.0 μM AChE Ki = 15.4 μM AChE Ki = 28.7 μM AChE Ki = 26.8 μM
MAO-A IC50 = 0.040 μM MAO-A IC50 = 29.0 μM MAO-A IC50 = 19.0 μM MAO-A IC50 = 37.4 μM
MAO-B IC50 = 33.0 μM MAO-B IC50 = 28% at 30 μM MAO-B IC50 = 14.7 μM MAO-B IC50 = 65.5 μM
basis of such observations, iron chelation has the potential to iron-chelating and/or antioxidant properties (Fig. 9) by combining
prevent ROS formation through Fenton reaction [83], the the iron-chelating and antioxidant 8-hydroxyquinoline scaffold of
consequent oxidative stress and the aggregation of -synuclein [84]. VK-28 (10) with a propargylamino group, which, along with MAO
Therefore metal chelation might represent a profitable approach to inhibition, could offer an additional neuroprotective effect [85].
efficiently target PD. Moreover, antioxidant compounds that are VK-28 has a potency for iron chelation equivalent to that of the
able to reduce the rate of formation of toxic ROS might play a role prototype iron chelator, desferal (Table 2) [85]. In contrast to
in PD. desferal, this iron-chelator was able to protect in vivo neurons from
Over the years the pivotal role of MAO-Is in PD therapy has toxicity deriving from 6-OHDA and MPTP neurotoxins in rats,
gained a growing consensus, since these drugs are able to limit showing a favourable blood-brain barrier crossing capability [86].
dopamine depletion. More recently, a strict connection of increased Among these novel hybrid derivatives, two compounds, namely
MAO activity with high iron levels and oxidative stress conditions HLA20 (11) and M30 (12) stand out for their highly relevant
has been postulated. Whether these mechanisms are really causative biological activities [87]. In addition to their chelating power very
or are manifestations of an ongoing neurotoxic cascade is still under close to that of desferal, as measured in Fe2+-induced calcein
debate. fluorescence quenching assays [85], both compounds inhibited
The multifaceted pathogenesis of PD prompted researchers to lipids peroxidation with IC50s in the low micromolar range (likely
develop therapeutic agents able to interfere simultaneously with through iron complexation) and showed higher MAO inhibitory
different targets in order to ameliorate the unsatisfactory current potency and brain permeability than VK28. The relative cell
pharmacological treatments. Indeed, a multipotent molecule with a permeability of 11 and 12 was measured through a chelator-induced
potential in PD can be obtained by the combination of appropriate calcein fluorescence enhancement within the iron-quenched calcein
biological activities including an iron-chelating activity and a ROS assay [85]. These multipotent ligands had a good permeability in
level reduction by radical scavenging mechanisms or throughout K562 cells that could be correlated to their favourable lipophilicity
MAO inhibition. as suggested by experimental logD determination. Further analyses
are needed to clarify their antioxidant profile that could be ascribed
A multi-target ligand design approach has been applied by to two possible mechanisms, that is the interference with Fenton
Youdim and co-workers to obtain MAO-Is endowed with additional reaction and the radical scavenging properties. HLA20 (11) metal-
O O O O O
* CH3SO3H
H2N N N N N N
5 2 H 5 H 5
2
OH OH OH
Desferal
OH
N N
H
N N N N
N N N N
OH OH OH OH
Fig. (9). 8-Hydroxyquinolines 10-13 with MAO inhibitory, metal-chelating and/or antioxidant activities.
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4577
of chelators in Fe2+-quenched calcein fluorescence test. Fe2+ binding affinity is inversely proportional to [M]1/2 value. dn.d. = not detected.
complexing property was more selective for iron than copper as MAO-inhibitory activity with the iron chelating and antioxidant
detected by spectrophotometric methods [85]. To investigate the properties by limiting two leading causes of ROS-related oxidative
radical-trapping capability of 11, electron paramagnetic resonance stress might result in clinically relevant beneficial activities even
(EPR) spectra were registered with different concentrations of superior to rasagiline.
scavenger in the presence of 5,5´-dimethyl-1-pyrroline-N-oxide A further development of these 8-hydroxyquinoline-containing
(DMPO) as a spin trap [87]. The concentration-dependent reduction metal chelators was focused on the improvement of their
of the DMPO-·OH spin adduct signal in a H2O2 photolysis system pharmacokinetic properties, such as CNS permeability and on the
clearly indicated the ability of 11 to trap directly hydroxyl radicals. amelioration of their toxicity profile. Moreover a higher metal
Compounds M30 (12) and M30A (13) showed radical- selectivity was pursued to avoid an indiscriminate interference with
scavenging properties (data not shown) similar to 11 [87]. HLA20 different metal ions pools, limiting their several important
(11) was a moderate MAO-I, less active but more MAO-B selective physiological functions.
than M30. On the other hand, both M30 and its demethylated
derivative M30A showed moderate selectivity for MAO-A in vitro N
and in vivo. Their inhibition was time-dependent and of a suicide
type. Within this 8-hydroxyquinoline series, M30 is worth noting. It
proved to be a very potent albeit not selective MAO inhibitor with
potencies in the nanomolar range. Interestingly, M30 showed an in
vivo MAO inhibition profile similar to ladostigil (5b). M30 acts as a N
brain permeable MAO-A and -B inhibitor without significant O O
effects on MAO activity in the liver and small intestine [88]. As a
consequence, M30 is able to enhance 5-HT and adrenaline neuronal N
transmission, adding an antidepressant effect to its pharmacological
profile. The prominent, but still unclarified, central and unselective (14)
MAO inhibition of M30 explains the lack of cardiovascular adverse AChE IC50 = 0.52 M
effects linked to tyramine potentiation. BChE IC50 = 44.9 M
MAO-A IC50 = 0.0077 M
Both M30 and M30A are metabolically transformed into active MAO-B IC50 = 7.90 M
propargylaminic metabolites that block the MAO catalytic activity
upon binding irreversibly and covalently to the prosthetic flavin Fig. (10). Multifunctional pro-chelator and MAO-AChE inhibitor 14 [91].
cofactor, FAD. The well-documented neuroprotective activity
associated to a propargylamino group, and unrelated to MAO A rational strategy to improve the drug-like properties of metal-
inhibition [89], claimed for a deeper exploitation of the potential chelators is based on a prodrug or on a neutral amino acid
use of these multifunctional compounds to prevent neuronal cell conjugation approach. To reduce citotoxicity and enhance
death on different in vitro and in vivo models. Concerning the lipophilicity, a site activated pro-chelator of M30 was designed by
neuroprotective activity of HLA20, cell death induced by 6-OHDA masking the 8-OH group of the quinoline moiety with a carbamate
under oxidative stress conditions was studied in vitro using a PC12 group (Fig. 10) [91]. In addition, this structural modification holds a
cells model [87]. The neuroprotective power of HLA20 might be potentially increased AChE targeting. The resulting compound (14)
ascribed to the combination of its multiple and different was evaluated to determine its chelating properties and its ability to
biochemical properties, namely iron-chelation, MAO-B inhibition inhibit both MAO and AChE in rat brain homogenates. As
and antioxidant activity. As for HLA20, a similar neuroprotective expected, compound 14 per se was not able to chelate biometals but
ability against 6-OHDA toxic insults was observed for M30 [87]. In was a potent and selective inhibitor of AChE (versus BChE) and
a neurorescue trial performed on SH-SY5Y neuroblastoma cell MAO-A (versus MAO-B). The central action of AChE, that is
lines under serum deprivation conditions, M30 decreased apoptosis located in different brain areas, allows to unmask the hydroxyl
likely through a reduced iron-promoted ROS production. In group of 14 upon the carbamylation of the catalytic serine thus
addition, M30 is able to induce neuronal differentiation, blocking releasing M30 and restoring the metal-chelating ability of the
cell cycle in G0/G1 phase [90]. Furthermore, in SH-SY5Y cells molecule. UV-visible spectral bands shifts of 14 were observed
M30 proved to reduce APP expression and shift APP processing upon AChE-activation of the pro-chelator in the presence of metal
preferentially towards the non-amyloidogenic pathways [90]. Taken salts, thus proving its ability to chelate Fe, Cu and Zn ions. The
together, these interesting features suggested M30 as a very pronounced selectivity of this pro-chelator towards AChE may be
promising molecule for the treatment of NDs, such as PD and AD, indicative of a safer profile, since it could reduce the toxicity
characterized by oxidative stress and iron dysregulation. In addition associated to the administration of non-selective AChE inhibitors as
to the neuroprotective and neurorescue effects mainly triggered by tacrine, whose hepatotoxicity is attributed to some extent also to its
the presence of the propargylamino moiety, the combination of
4578 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
OH
OH
HO O
R
OH O
low selectivity. In addition, the increased lipophilic character principle of Rhizoma acori graminei (RAG), a botanical remedy
allows the compound to cross the blood-brain barrier massively described in Chinese pharmacopoeias and used as a palliative
thus obtaining a high CNS targeting while the low affinity for treatment of AD cognitive dysfunctions. This compound holds an
BChE minimizes the peripheral cleavage and the unwanted antioxidant activity that could be ascribed to the phenolic structure.
interference with metal homeostasis in peripheral tissues. It has been reported that 16 inhibits Fe2+-ascorbic acid induced lipid
peroxidation in a dose dependent manner, producing a 76%
Compounds with Dual MAO Inhibitory-Antioxidant (Radical reduction at a concentration of 250 μM [95]. To clarify the
Scavenging) Activity mechanisms driving the antioxidant properties of 16, EPR spin
trapping experiments were performed. Eugenol antioxidant activity
As already discussed, one of the main factors triggering or is linked to its ability of trapping directly some ROS, such as
sustaining NDs may be the formation of free toxic radicals that superoxide and hydroxyl radicals, rather than by acting as a free
contributes to neuronal impairments by promoting abnormal radical chain-reaction breaker. In addition, eugenol can reduce ROS
oxidized species in different biomacromolecules (e.g., lipids, production and relieve oxidative stress conditions through another
proteins and nucleic acids). The oxidative stress cascade can be mechanism, that is a moderate and competitive inhibition of MAO
broken upstream, preventing the formation of hydroxyl radicals, or, catalytic activity. In fact, 16 inhibits preferentially human
as an alternative, by sequestering intermediate radicals with recombinant MAO-A (Ki = 26.0 μM) over MAO-B (Ki = 211 μM)
appropriate radical scavengers. Since a runaway free radical [96]. This dual activity of eugenol may represent a valuable feature
production begins working in brain tissues suffering from in the treatment of NDs.
neurotoxicity and basal MAO catabolic activity contributes to ROS
production, the simultaneous inhibition of MAOs and the free Compounds with Dual MAO-NOS Inhibitory Activity
radical-scavenging activity through a single molecular entity could
potentially represent synergic activities that might result useful in Different studies highlighted the effect of oxidative stress in
the treatment or prevention of NDs. promoting mitochondrial dysfunction, inflammation processes and
nitric oxide (NO) toxicity in PD. Nitric oxide is a cellular signalling
Flavonoids represent a class of compounds widely diffuse in mediator involved in several physiological and pathological
nature that are able to mediate different pharmacological actions, conditions [97]. Among others, NO regulates smooth muscle
often through antioxidant mechanisms. Four flavonoids, quercitrin relaxation, platelet aggregation, penile erection, macrophages
(15a), isoquercitrin (15b), rutin (15c) and quercetin (15d; Fig. 11), activities, brain functionalities (e.g., learning and memory).
have been isolated from the leaves of Melastoma candidum D. Don Notwithstanding, NO is a free radical species in nature and its
and investigated for their ability to inhibit MAOs and to scavenge overproduction may lead to harmful oxidative damages. NO can act
free radicals [92]. The kinetic analysis of MAO-B inhibition either as a weak oxidant or as reductive species and can exist in
indicated a mixed-type mechanism, with Ki values in the low three redox forms, namely nitric oxide (NO), nitrosonium (NO+)
micromolar range. Flavonoids 15 were endowed with hydroxyl and nitroxyl anion (NO–) [98]. It has been hypothesized that NO
radical scavenging activity as assessed by an EPR spin trapping toxicity is exerted through the production of reactive nitrogen
technique. More recent results show that quercetin (15d) is a potent species (RNS; e.g., ·NO2, N2O3, HNO2) and by the reaction with
and selective MAO-A inhibitor with an IC50 = 0.010 μM [93]. In superoxide to form peroxynitrite anion (ONOO), that is a strong
contrast with previous findings, it has been recently reported that oxidizing agent involved in protein oxidation under physiological
15d weakly inhibits MPTP bioactivation (33% at 10 μM conditions (Scheme 2) [99].
concentration) and this suggests also a limited inhibition of the RNS and NO represent potentially mutagenic species able to
MAO-B activity [94]. react with nucleic acids bases through nitration, nitrosation and
O deamination reactions [100]. Thus the block of the production of
nitric oxide in appropriate brain areas might be an important goal in
the search of new agents able to halt or reverse neurodegenerative
HO
cascades. To this end, one feasible approach has been envisaged to
Eugenol (16) discovery molecules with RNS scavenging property. In addition,
MAO-A Ki = 26.0 μM attention has been focused also on the design of molecules able to
MAO-B Ki = 211 μM inhibit the enzyme responsible for NO endogenous production, that
Fig. (12). Eugenol (16), a MAO inhibitor with antioxidant activity [96]. is the nitric oxide synthase (NOS) [101]. This enzyme catalyzes the
endogenous NADPH-dependent transformation of L-arginine to
Eugenol (4-allyl-2-methoxyphenol, 16) is the major component citrulline and exists in three different isoforms: neuronal NOS
of clove, cinnamon, basil, and nutmeg oils and the major active (nNOS), endothelial NOS (eNOS) and cytokine-inducible NOS
(iNOS). Thus, the reduction of the harmful NO-related biochemical
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4579
thiols
(RSH) GSH
N2O3 RSNO GSNO
RSH
O2
L-arginine NOS NO
O2
ONOO H+ NO2
ONOOH OH +
citrulline
OH
HNO2
effects along the MAO-B inhibition might represent an original way showed enzymatic and antioxidant activities comparable to its
to slow down the rate of neurodegeneration. parent compound, suggested PF9601N as a promising
neuroprotective agent for the prevention and/or cure of PD.
R2
O
O N R3
N
N Cl
N
R1 O N N
PF9601N (17) FA72 (18) (19)
R1 = R2 = H R1 = R2 = R3 = H MAO-B Ki = 0.181 M
R3 = _CH2C CH NOS IC50 = 1057 M
Br
Cl
O
O
N
N N (E)
N
(E)
N (E)
O N N
O N
Fig. (17). Caffeine derivatives 23-24 with dual MAO-I and adenosine A2A receptor antagonist activity [126].
targets that could be modulated in order to prevent, retard or halt particular attention to the effects of the styryl group and its
the progression of the neurodegenerative cascade leading to PD. substitution pattern [126]. Within this new series of compounds, the
Antagonists of adenosine receptors that are selective for the A2A phenyl and benzyl congeners resulted less active towards MAO-B.
subtype displayed a neuroprotective action [119] and were able to The application of a vinilogous approach led to the (E,E)-8-(4-
prevent the onset of dyskinesia associated with long-term levodopa phenylbutadien-1-yl)caffeine derivatives, among which 3’-
treatment [120]. Thereby, their effects are additive to those of halosubstituted compounds showed outstanding MAO-B affinity
dopamine-replacement therapy and may allow a reduction of and potent A2A receptor antagonism, being both Kis in the
levodopa dosage regimen thus limiting the occurrence of adverse nanomolar range. The introduction of bromine in 3’-position led to
effects. For these reasons, A2A antagonists emerged as a new class the most active dual-targeting derivative (24), that showed an
of compounds with a potential value for neuroprotection and impressive high potency at both targets (Ki = 21.9 and 59.1 nM at
symptomatic relief of motor deficits associated with PD [121]. As MAO-B and A2A, respectively). Further developments of these
previously mentioned, since MAO-B is the prevalent isoform compounds may be hampered by their likely low configurational
located in human basal ganglia and evidence of its, age-related, stability and high photosensitivity.
increase has been reported by many authors [122], also MAO-B
inhibitors were considered a therapeutic opportunity and indeed are MAO-Is with APP Processing Modulatory Activity
used as adjutants of levodopa in the replenishment of dopamine The proteolytic cleavage of APP can be modulated at different
levels. levels by intracellular second messengers. In this context, a pivotal
On this basis, research efforts have been directed to the modulating role seems to be played by MAPK through the
discovery of novel molecular entities with a dual action, that is activation of MEK/ERK signalling pathways [127]. It has been
MAO-B inhibition and A2A receptor antagonism, that holds a reported that rasagiline (1) and ladostigil (5b) can stimulate the
potential in the treatment of PD. Since experimental evidence release of the neuroprotective soluble form of amyloid precursor
showed that caffeine, a non-selective A1/A2A receptor antagonist, is protein (sAPP) by influencing the rate of PKC- and MEK-
able to protect from MPTP-induced neurotoxicity in mouse model related processing [128].
of PD [111], closely related heterocyclic derivatives were evaluated On the other hand, the reduction of toxic A1-42 production can
too. Among them, (E)-8-(3-chlorostyryl)-caffeine (23, CSC, Fig. be achieved in a straightforward manner, through - and -secretase
17) [123] emerged as a potent and selective A2A antagonist inhibitors, or indirectly, through the activation of PKC- and MEK-
endowed with neuroprotective properties, that could be related to its dependent cleavage. The combination in one compound of some of
high affinity for MAO-B. Interestingly, CSC effect on the inhibition these biological activities, along with MAO-related ROS reduction,
of MAO-A was not significant [124]. Thus, different compounds may synergistically favour the APP non-amyloidogenic proteolysis,
bearing a (E)-8-styrylxanthine scaffold were synthesized and or block the amyloidogenic one, thus deserving great attention for
evaluated for a dual MAO-B/A2A targeting activity [125]. From the the prevention and treatment of AD.
analysis of SARs, it emerged that both biological actions were
favourably influenced by the introduction of a methyl group on the To achieve this goal, two series of 7-carbamoyl-1,2,3,4-
xanthine N-7. The presence of an electron-donating group on the tetrahydroisoquinolines (25) were designed and synthesized as
styryl moiety strongly enhances MAO-B affinity, while reducing cyclic congeners of ladostigil (Fig. 18) [129]. These sets of
A2A receptor antagonism not so dramatically. Since these novel derivatives differ for the substituent at basic nitrogen, where the
compounds proved to be from moderate to good MAO-B inhibitors propargyl group was replaced by a more sterically hindered and
and A2A receptor antagonists, they deserved further investigations lipophilic cyclopropylmethyl group. All the synthesized derivatives
to gain deeper insights into the molecular determinants of their were evaluated as MAO inhibitors showing moderate IC50 values
dual-targeting activity. With this purpose, the molecular framework ranging from 11.6 to 21.5 μM by using rat brain homogenates
of the lead compound (CSC) was properly modified paying (Table 3). Since cyclopropyl derivatives 25b-c were the most active
O O
N N
R O R O
Fig. (18). 7-Carbamoyl-1,2,3,4-tetrahydroisoquinoline derivatives 25 with dual MAO-I and APP processing modulator activity [129].
4582 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
compounds for the inhibition of -secretase enzymatic activity, showing an anti-inflammatory action [136]. In addition,
some of these compounds were tested in -cells to detect their pretreatment of mice with pioglitazone reduced MPTP toxicity
influence on ERK signalling pathways. Interestingly, the most [137] and dopaminergic neuronal loss [138]. The protective action
potent MAO-B inhibitor (31b) was also able to inhibit -secretase against MPTP toxicity is mediated by the inhibition of MAO-B
and activate ERK pathways more strongly than rasagiline, showing [139]. Pioglitazone showed a potent affinity in vitro towards human
promising potential against AD [129]. recombinant MAO-B (IC50 = 220 nM) and its inhibitory efficacy
was proved also in ex vivo studies on male C57BL6/J mice. The
Repositioning of Known Drugs as Multitarget Ligands with synergy of MAO-B inhibitory property and the ability to modulate
MAO Inhibitory Activity inflammatory responses in neurodegenerative processes through the
activation of PPAR [140] increases the interest of this compound
A recent research strategy in drug discovery, named “drug as a potential therapeutic agent in NDs.
repositioning” or “drug repurposing” and focused on the discovery
of new drugs for the therapy of neglected or orphan diseases, CONCLUSIONS
consists in the analysis of approved drugs in the search of novel and The rational design, synthesis and bio-pharmacological
“hidden” pharmacological activities [4b]. Following this approach, evaluation of multipotent ligands addressing MAO inhibition
two known drugs have been proved to act as multi-target ligands among other targeted pharmacological activities in NDs has been a
with interesting MAO inhibitory activities and a potential in NDs: challenging research activity that led to the discovery of new
the antiepileptic drug zonisamide and the antidiabetic agent interesting bioactive compounds that deserve further development
pioglitazone (Fig. 19). towards pre-clinical and clinical trials. Although strong efforts have
Zonisamide (26) is an FDA-approved drug for the treatment of been produced by several research groups in the rational molecular
epilepsy that is also being used as an adjuvant in the therapy of PD design and in the explorative screening of large molecular libraries
[130]. Its antiepileptic action is exerted through the blockade of to discover new promising multi-targeting agents for NDs, few
voltage-dependent Na+ channels and T-type Ca2+ channels [131]. It works succeeded in finding compounds with comparable potencies
has been reported that zonisamide is able to protect nigrostriatal or adequate potency ratio towards the addressed targets. These
neurons from neurotoxic 6-OHDA insults [132], likely through a difficulties arose mainly from the complexity of modulating
radical-scavenging mechanism [133]. Its ability to reduce oxidative appropriately and in a simultaneous way two or more different
stress prompted researchers to examine the effects of zonisamide in targets with a single molecule.
animal models of PD and to define its mechanisms of action [134]. Unfortunately, the structure-based design of a multipotent
Zonisamide showed neuroprotection against MPTP toxicity in male ligand is possible only in limited cases, since the 3D structures of
Swiss Webster mice and moderately inhibited mouse brain the targeted biomolecules are not always available. The lack of
homogenates MAO-B activity in vitro with an IC50 = 25 μM and a information about the binding mode of a multipotent ligand into the
reversible mechanism of action as assessed by ex vivo studies in active sites of the diverse biological targets may force the
mice [134]. No inhibition of MAO-A activity was observed. More researcher to a sort of “blind design” characterized by a long
recently, zonisamide complex with human MAO-B has been sequence of trials and errors. In these cases, indirect ligand-design
solved, thus allowing a deeper comprehension of the binding methods may be profitably applied through the derivation of
interactions at the active site of the enzyme [135]. Taken together QSAR, [141] 3D-QSAR [142] and pharmacophore models [143]
these findings underline the multi-target activity of zonisamide and that may allow a more rational and successful design of a
its potential use in PD, for a symptomatic improvement of motor multipotent ligand. A more detailed knowledge of the main binding
deficits and a neuroprotective action. interactions occurring with the different biological targets is instead
The peroxisome proliferator-activated receptor- (PPAR) possible through structure-based computational methods which may
agonist pioglitazone (27) is a brain-permeable antidiabetic drug lead to an unequivocal identification of the molecular determinants
belonging to the thiazolidinedione family. It has been demonstrated responsible for the activity at each single target and an easier
that it performs a neuroprotective effect in animal models of AD development of a multi-target pharmacophore model.
O
S NH2 S
O O
HN
N O O N
O
Fig. (19). “Repurposed drugs” inhibiting MAO-B with a potential in NDs [134, 139].
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4583
ROS = Reactive oxygen species [21] Tuteja, N.; Ahmad, P.; Panda, B.B.; Tuteja, R. Genotoxic stress in plants:
shedding light on DNA damage, repair and DNA repair helicases. Mut. Res-
PPAR = Peroxisome proliferator-activated receptor- Rev. Mutat., 2009, 681, 134-149.
[22] Jomova, K.; Vondrakova, D.; Lawson, M.; Valko, M. Metals, oxidative
PKC = Protein kinase C stress and neurodegenerative disorders. Mol. Cell. Biochem., 2010, 345, 91-
PKC = Protein kinase C 104.
[23] Gaeta, A.; Hider, R.C. The crucial role of metal ions in neurodegeneration:
sAPP = Soluble amyloid precursor protein the basis for a promising therapeutic strategy. Br. J. Pharmacol., 2005, 146,
1041-1059.
sAPP = Soluble amyloid precursor protein [24] Soto, C. Unfolding the role of protein misfolding in neurodegenerative
diseases. Nat. Rev. Neurosci., 2003, 4, 49-60.
SARs = Structure-affinity relationships [25] Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in
SET = Single electron transfer neurodegenerative diseases. Nature, 2006, 443, 787-795.
[26] Sterling, J.; Veinberg, A.; Lerner, D.; Goldenberg, W.; Levy, R.; Youdim,
SIN-1 = 3-Morpholinosydnonimine M.; Finberg, J. (R)(+)-N-propargyl-1-aminoindan (rasagiline) and
derivatives: Highly selective and potent inhibitors of monoamine oxidase B.
SOD = Superoxide dismutase J. Neural Transm.-Supp., 1998, 52, 301-305.
[27] a) Finberg, J.P.; Lamensdorf, I.; Commissiong, J.W.; Youdim, M.B.H.
SSRs = Structure-selectivity relationships Pharmacology and neuroprotective properties of rasagiline. J. Neural
SSRIs = Selective serotonin reuptake inhibitors Transm.-Supp., 1996, 48, 95-101; b) Finberg, J.P.; Lamensdorf, I.;
Weinstock, M.; Schwartz, M.; Youdim, M.B.H. Pharmacology of rasagiline
UPS = Ubiquitine-proteasome system (N-propargyl-1R-aminoindan). Adv. Neurol., 1999, 80, 495-499; c) Youdim,
M.B.H.; Bakhle, Y.S. Monoamine oxidase: isoforms and inhibitors in
Parkinson’s disease and depressive illness. Br. J. Pharmacol., 2006, 147,
REFERENCES S287-S296; d) Youdim, M.B.H.; Edmondson, D.; Tipton, K.F. The
therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci.,
[1] Petrelli, A.; Giordano, S. From single- to multi-target drugs in cancer 2006, 7, 295-309.
therapy: when aspecificity becomes an advantage. Curr. Med. Chem., 2008, [28] Reynolds, G.P.; Riederer, P.; Sandler, M.; Jellinger, K.; Seemann, D.
15, 422-432. Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain
[2] Korcsmáros, T.; Szalay, M.S.; Böde, C.; Kovács, I. A.; Csermely, P. How to after (L)-deprenyl administration. J. Neural Transm., 1978, 43, 271-277.
design multi-target drugs: Target search options in cellular networks. Expert [29] a) Finberg, J.P.; Tenne, M.; Youdim, M.B.H. Tyramine antagonistic
Opin. Drug Disc., 2007, 2, 1-10. properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type
[3] Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple B. Br. J. Pharmacol., 1981, 73, 65-74; b) Simpson, L.L. Evidence that
ligands. Drug Discov. Today, 2004, 9, 641-651. deprenyl, a type B monoamine oxidase inhibitor, is an indirectly acting
[4] Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; sympathomimetic amine. Biochem. Pharmacol., 1978, 27, 1591-1595.
Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat [30] Maruyama, W.; Takahashi, T.; Youdim, M.B.H.; Naoi, M. The anti-
neurodegenerative diseases. J. Med. Chem., 2008, 51, 347-372. parkinson drug, rasagiline, prevents apoptotic DNA damage induced by
[5] a) Ekins, S.; Williams, A.J.; Krasowski, M.D.; Freundlich, J.S. In silico peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells. J.
repositioning of approved drugs for rare and neglected diseases. Drug Neural Transm., 2002, 109, 467-481.
Discov. Today, 2011, 16, 298-310; b) Ashburn, T.T.; Thor, K.B. Drug [31] Heikkila, R.E.; Duvoisin, R.C.; Finberg, J.P.; Youdim, M.B.H. Prevention of
repositioning: identifying and developing new uses for existing drugs. Nat. MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective
Rev. Drug Discov., 2004, 3, 673-683. inhibitors of monoamine oxidase-B. Eur. J. Pharmacol., 1985, 116, 313-317.
[6] Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug [32] Maruyama, W.; Akao, Y.; Youdim, M.B.H.; Naoi, M. Neurotoxins induce
discovery paradigm. J. Med. Chem., 2005, 48, 6523-6543. apoptosis in dopamine neurons: protection by N-propargylamine-1(R)- and
[7] Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, (S)-aminoindan, rasagiline and TV1022. J. Neural Transm.-Supp., 2000, 60,
C.A.M. Molecular hybridization: a useful tool in the design of new drug 171-186.
prototypes. Curr. Med. Chem., 2007, 14, 1829-1852. [33] Akao, Y.; Maruyama, W.; Shimizu, S.; Yi, H.; Nakagawa, Y.; Shamoto-
[8] Strolin-Benedetti, M.; Tipton, K.F.; Whomsley, R. Amine oxidases and Nagai, M.; Youdim, M.B.; Tsujimoto, Y.; Naoi, M. Mitochondrial
monooxygenases in the in vivo metabolism of xenobiotic amines in humans: permeability transition mediates apoptosis induced by N-methyl-(R)-
has the involvement of amine oxidases been neglected? Fundam. Clin. salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and
Pharmacol., 2007, 21, 467-479. rasagiline, N-propargyl-1(R)- aminoindan. J. Neurochem., 2002, 82, 913-
[9] Edmondson, D.E.; Mattevi, A.; Binda, C.; Li, M.; Hubalek, F. Structure and 923.
mechanism of monoamine oxidases. Curr. Med. Chem., 2004, 11, 1983- [34] Huang, W.; Chen, Y.; Shohami, E.; Weinstock, M. Neuroprotective effect of
1993. rasagiline, a selective monoamine oxidase-B inhibitor, against closed head
[10] Nandigama, R.K.; Edmondson, D.E. Structure-activity relations in the injury in the mouse. Eur. J. Pharmacol., 1999, 366, 127-135.
oxidation of phenethylamine analogues by recombinant human liver [35] Youdim, M.B.H.; Gross, A.; Finberg, J.P.M. Rasagiline [N-propargyl-
monoamine oxidase A. Biochemistry, 2000, 39, 15258-15265. 1R(+)aminoindan], a selective and potent inhibitor of mitochondrial
[11] Grimsby, J.; lan, N.C.; Neve, R.; Chen, K.; Shih, J.C. Tissue distribution of monoamine oxidase B. Br. J. Pharmacol., 2001, 132, 500-506.
human monoamine oxidase-A and oxidase-B messenger-RNA. J. [36] Youdim, M.B.H.; Weinstock, M. Molecular basis of neuroprotective
Neurochem., 1990, 55, 1166-1169. activities of rasagiline and the anti Alzheimer drug, TV3326, [(N-propargyl-
[12] Fowler, C.J.; Ross, S.B. Selective inhibitors of monoamine oxidase A and B: (3R)-aminoindan-5-yl)-ethyl methyl carbamate]. Cell. Mol. Neurobiol., 2002,
biochemical, pharmacological, and clinical properties. Med. Res. Rev., 1984, 21, 555-573.
4, 323-358. [37] a) Weinreb, O.; Bar-Am, O.; Amit, T.; Chillag-Talmor, O.; Youdim, M.B.H.
[13] Egashira, T. Studies on monoamine oxidase. XVIII. Enzymatic properties of Neuroprotection via pro-survival protein kinase C isoforms associated with
placental monoamine oxidase. Jap. J. Pharmac., 1976, 26, 493-500. Bcl-2 family members. FASEB J., 2004, 18, 1471-1473; b) Tatton, W.G.;
[14] Donnelly, C.H.; Murphy, D.L. Substrate- and inhibitor-related characteristics Chalmers-Redman, R.M.; Ju, W.J.; Mammen, M.; Carlile, G.W.; Pong,
of human platelet monoamine oxidase. Biochem. Pharmacol., 1977, 26, 852- A.W.; Tatton, N.A. Propargylamines induce antiapoptotic new protein
858. synthesis inserum-and nerve growth factor(NGF)-withdrawn, NGF-
[15] Saura, J.; Kettler, R.; Da Prada, M.; Richards, J.G. Quantitative enzyme differentiated PC-12 cells. J. Pharmacol. Exp. Ther., 2002, 301, 753-764; c)
radioautography with 3H-Ro 41-1049 and 3HRo 19-6327 in vitro: Bar-Am, O.; Weinreb, O.; Amit, T.; Youdim, M. B. Regulation of Bcl-2
localization and abundance of MAO-A and MAO-B in rat CNS, peripheral family proteins, neurotrophic factors, and APP processing in the neurorescue
organs, and human brain. J. Neurosci., 1992, 12, 1977-1999. activity of propargylamine. FASEB J., 2005, 19, 1899-1901.
[16] a) Youdim, M.B.; Edmondson, D.E.; Tipton, K.F. The therapeutic potential [38] a) Maruyama, W.; Akao, Y.; Youdim, M.B.H.; Davis, B.A.; Naoi, M.
of monoamine oxidase inhibitors. Nat. Rev. Neurosci., 2006, 7, 295-309; b) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug,
Yamada, M.; Yasuhara, H. Clinical pharmacology of MAO inhibitors: safety rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate
and future. Neurotoxicology, 2004, 25, 215-221. dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-
[17] Finberg, J.P.M.; Youdim, M.B.H. Selective MAO-A and MAO-B inhibitors: methyl-(R)-salsolinol. J. Neurochem., 2001, 78, 727-735; b) Youdim,
their mechanism of action and pharmacology. Neuropharmacology, 1983, M.B.H. Rasagiline: an anti-Parkinson drug with neuroprotective activity.
22, 441-446. Expert Rev. Neurother., 2003, 3, 737-749.
[18] Fernandez, H.H.; Chen, J.J. Monoamine oxidase-B inhibition in the [39] a) Yogev-Falach, M.; Amit, T.; Bar-Am, O.; Youdim, M.B.H. The
treatment of Parkinson’s disease. Pharmacotherapy, 2007, 27, S174-S185. importance of propargylamine moiety in the anti-Parkinson drug rasagiline
[19] Wimbiscus, M.; Kostenko, O.; Malone, D. MAO inhibitors: risks, benefits, and its derivatives for MAPK-dependent amyloid precursor protein
and lore. Cleve. Clin. J. Med., 2010, 77, 859-882. processing. FASEB J., 2003, 17, 2325-2327; b) Bar-Am, O.; Yogev-Falach,
[20] Hauser, R.A. Early pharmacologic treatment in Parkinson’s disease. Am. J. M.; Amit, T.; Sagi, Y.; Youdim, M.B.H. Regulation of protein kinase C by
Manag. Care, 2010, 16, S100-S107.
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4585
the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in potent and selective dual binding site acetylcholinesterase inhibitors.
vivo. J. Neurochem., 2004, 89, 1119-1125. ChemMedChem, 2010, 5, 1616-1630.
[40] a) Esch, F.S.; Keim, P.S.; Beattie, E.C.; Blacher, R.W.; Culwell, A.R.; [65] Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; Goldenberg,
Oltersdorf, T.; McClure, D.; Ward, P.J. Cleavage of amyloid beta peptide W.; Miskolczi, I.; Molnar, S.; Rantal, F.; Tamas, T.; Toth, G.; Zagyva, A.;
during constitutive processing of its precursor. Science, 1990, 248, 1122- Zekany, A.; Lavian, G.; Gross, A.; Friedman, R.; Razin, M.; Huang, W.;
1124; b) Sisodia, S.S.; Koo, E.H.; Beyreuther, K.; Unterbeck, A.; Price, D.L. Krais, B.; Chorev, M.; Youdim, M.B.H.; Weinstock, M. Novel dual
Evidence that beta amyloid protein in Alzheimer’s disease is not derived by inhibitors of AChE and MAO derived from hydroxy aminoindan and
normal processing. Science, 1990, 248, 492-495. phenethylamine as potential treatment for Alzheimer’s disease. J. Med.
[41] Bar-Am, O.; Weinreb, O.; Amit, T.; Youdim, M.B.H. The neuroprotective Chem., 2002, 45, 5260-5279.
mechanism of 1-(R)-aminoindan, the major metabolite of the anti- [66] Weinstock, M.; Gorodetsky, E.; Wang, R.H.; Fross, A.; Weinreb, O.;
parkinsonian drug rasagiline. J. Neurochem., 2010, 112, 1131-1137. Youdim, M.B.H. Limited potentiation of blood pressure response to oral
[42] Chen, J.J.; Swope, D.M. ; Dashtipour, K. Comprehensive review of tyramine by brain-selective monoamine oxidase A–B inhibitor, TV-3326 in
rasagiline, a second-generation monoamine oxidase inhibitor, for the conscious rabbits. Neuropharmacology, 2002, 43, 999-1005.
treatment of Parkinson’s disease. Clin. Ther., 2007, 29, 1825-1849. [67] Weinstock, M.; Gorodetsky, E.; Poltyrev, T.; Gross, A.; Sagi, Y.; Youdim,
[43] Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allg. Z. M.B.H. A novel cholinesterase and brain-selective monoamine oxidase
Psychiat., 1907, 64, 146-148. inhibitor for the treatment of dementia comorbid with depression and
[44] Querfurth, H.W.; LaFerla, F.M. Mechanisms of disease: Alzheimer’s Parkinson's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2003,
disease. New Engl. J. Med., 2010, 362, 329-344. 27, 555-561.
[45] Sivaprakasam, K. Towards a unifying hypothesis of Alzheimer’s disease: [68] Sagi, Y.; Weinstock, M.; Youdim, M.B.H. Attenuation of MPTP-induced
cholinergic system linked to plaques, tangles and neuroinflammation. Curr. dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine
Med. Chem., 2006, 13, 2179-2188. oxidase inhibitor. J. Neurochem., 2003, 86, 290-297.
[46] Bolognesi, M.L.; Minarini, A.; Tumiatti, V.; Melchiorre, C. Progress in [69] Sagi, Y.; O. Weinreb, O.; Weinstock, M.; Youdim, M.B.H. Neuroprotective
acetylcholinesterase inhibitors for Alzheimer’s disease. Expert Opin. Ther. and neurorescue properties of rasagiline and TV3326 in MPTP model of
Pat., 2006, 16, 811-823. Parkinson’s disease. Neural Plasticity, 2001, 8, 197-198.
[47] Fisher, A.; Michaelson, D.M.; Brandeis, R.; Haring, R.; Chapman, S.; Pittel, [70] Weinstock, M.; Kirschbaum-Slager, N.; Lazarovici, P.; Bejar, C.; Youdim,
Z. M1 muscarinic agonists as potential disease-modifying agents in M.B.H.; Shoham, S. Neuroprotective effects of novel cholinesterase
Alzheimer's disease. Rationale and perspectives. Ann. N. Y. Acad. Sci., 2000, inhibitors derived from rasagiline as potential anti-Alzheimer drugs. Ann. N.
920, 315-320. Y. Acad. Sci., 2001, 939, 148-161.
[48] Inestrosa, N.C.; Dinamarca, M.C.; Alvarez, A. Amyloid–cholinesterase [71] Naoi, M.; Maruyama, W. Monoamine oxidase inhibitors as neuroprotective
interactions. FEBS J., 2008, 275, 625-632. agents in age-dependent neurodegenerative disorders. Curr. Pharm. Design,
[49] Martorana, A.; Esposito, Z.; Koch, G. Beyond the cholinergic hypothesis: do 2010, 16, 2799-2817.
current drugs work in Alzheimer's disease? CNS Neurosci. Ther., 2010, 16, [72] Gökhan, N.; Yesilada, A.; Uçar, G.; Erol, K.; Bilgin, A. 1-N-Substituted
235-245. thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: synthesis and evaluation as
[50] Frisardi, V.; Solfrizzi, V.; Imbimbo, P.B.; Capurso, C.; D'Introno, A.; MAO inhibitors. Arch. Pharm. Pharm. Med. Chem., 2003, 336, 362-371.
Colacicco, A.M.; Vendemiale, G.; Seripa, D.; Pilotto, A.; Capurso, A.; [73] Uçar, G.; Gökhan, N.; Yesilada, A.; Bilgin, A.A. 1-N-Substituted
Panza, F. Towards disease-modifying treatment of Alzheimer's disease: thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines: A novel cholinesterase and
drugs targeting –Amyloid. Curr. Alzheimer Res., 2010, 7, 40-55. selective monoamine oxidase B inhibitors for the treatment of Parkinson’s
[51] Evin, G.; Kenche, V.B. BACE inhibitors as potential therapeutics for and Alzheimer’s diseases. Neurosci. Lett., 2005, 382, 327-331.
Alzheimer's disease. Recent Pat. CNS Drug Discov., 2007, 2, 188-199. [74] a) Bruhlmann, C.; Marston, A.; Hostettmann, K.; Carrupt, P.A.; Testa, B.
[52] Lundkvist, J.; Naslund, J. Gamma-secretase: a complex target for Screening of non-alkaloidal natural compounds as acetylcholinesterase
Alzheimer’s disease. Curr. Opin. Pharmacol., 2007, 7, 112-118. inhibitors. Chem. Biodivers., 2004, 1, 819-829; b) Gnerre, C.; Thull, U.;
[53] Mason, J.M.; Kokkoni, N.; Stott, K.; Doig, A.J. Design strategies for anti- Gaillard, P.; Carrupt, P.-A.; Testa, B.; Fernandes, E.; Silva, F.; Pinto, M.;
amyloid agents. Curr. Opin. Struc. Biol., 2003, 13, 526-532. Pinto, M.M.M.; Wolfender, J.-L.; Hostettmann, K.; Cruciani, G. Natural and
[54] Lemere, C.A.; Masliah, E. Can Alzheimer disease be prevented by amyloid- synthetic xanthones as monoamine oxidase inhibitors: biological assay and
immunotherapy? Nat. Rev. Neurol., 2010, 6, 108-119. 3D-QSAR. Helv. Chim. Acta, 2001, 84, 552-570.
[55] Sun, A.Y.; Chen, Y.M. Oxidative stress and neurodegenerative disorders. J. [75] Jankovic, J. Parkinson’s disease: clinical features and diagnosis. J. Neurol.
Biomed. Sci., 1998, 5, 401-414. Neurosurg. Psychiatry, 2008, 79, 368-376.
[56] a) Delumeau, J.C.; Bentué-Ferrer, D.; Gandon, J.M.; Amrein, R.; Belliard, [76] Allain, H.; Bentué-Ferrer, D.; Akwa, Y. Disease-modifying drugs and
S.; Allain, H. Monoamine oxidase inhibitors, cognitive functions and Parkinson's disease. Prog. Neurobiol., 2008, 84, 25-39.
neurodegenerative diseases. J. Neural Transm. Suppl., 1994, 41, 259-266; b) [77] Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.-Y.; Trojanowski, J.Q.; Jakes,
Naoi, M.; Maruyama, W.; Akao, Y.; Yi, H.; Yamaoka, T. Involvement of R.; Goedert, M. -Synuclein in Lewy bodies. Nature, 1997, 388, 839-840.
type A monoamine oxidase in neurodegeneration: regulation of [78] Oueslati, A.; Fournier, M.; Lashuel, H.A. Role of post-translational
mitochondrial signaling leading to cell death or neuroprotection. J. Neural modifications in modulating the structure, function and toxicity of alpha-
Transm. Suppl., 2006, 71, 67-77. synuclein: implications for Parkinson's disease pathogenesis and therapies.
[57] Saura, J.; Luque, J.M.; Cesura, A.M.; Da Prada, M.; Chan-Palay, V.; Huber, Prog. Brain Res., 2010, 183, 115-145.
G.; Loffler, J.; Richards, J.G. Increased monoamine oxidase B activity in [79] Norris, E.H.; Giasson, B.I.; Ischiropoulos, H.; Lee, V.M. Effects of oxidative
plaque-associated astrocytes of Alzheimer brains revealed by quantitative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct
enzyme radioautography. Neuroscience, 1994, 62, 15-30. mechanisms of protein modifications. J. Biol. Chem., 2003, 278, 27230-
[58] a) Van der Schyf, C.J.; Geldenhuys, W.J.; Youdim, M.B.H. Multifunctional 27240.
drugs with different CNS targets for neuropsychiatric disorders. J. [80] Wang, X.; Moualla, D.; Wright, J.A.; Brown, D.R. Copper binding regulates
Neurochem., 2006, 99, 1033–1048; b) Youdim, M.B.H.; Buccafusco, J.J. intracellular alpha-synuclein localisation, aggregation and toxicity. J.
Multi-functional drugs for various CNS targets in the treatment of Neurochem., 2010, 113, 704-714.
neurodegenerative disorders. Trends Pharm. Sci., 2005, 26, 27-35. [81] Bisaglia, M.; Tessari, I.; Mammi, S.; Bubacco, L. Interaction between alpha-
[59] Fink, D.M.; Palermo, M.G.; Bores, G.M.; Huger, F.P.; Kurys, B.E.; synuclein and metal ions, still looking for a role in the pathogenesis of
Merriman, M.C.; Olsen, G.E.; Petko, W.; O’Malley, G.J. Imino 1,2,3,4- Parkinson's disease. Neuromol. Med., 2009, 11, 239-251.
tetrahydrocyclopent[b]indole carbamates as dual inhibitors of [82] Lv, Z.; Jiang, H.; Xu, H.; Song, N.; Xie, J. Increased iron levels correlate
acetylcholinesterase and monoamine oxidase. Bioorg. Med. Chem. Lett., with the selective nigral dopaminergic neuron degeneration in Parkinson's
1996, 6, 625-630. disease. J. Neural Transm., 2011, 118, 361-369.
[60] O’Malley, G.J.; Bores, G.; Huger, F.; Kuris, B.E.; Merriman, M.C.; Olsen, [83] Allsop, D.; Mayes, J.; Moore, S.; Masad, A.; Tabner, B.J. Metal-dependent
G.; Petko, W.; Palermo, M.G. Abstract of the 205th American Chemical generation of reactive oxygen species from amyloid proteins implicated in
Society National Meeting 1993, MEDI, abstract. neurodegenerative disease. Biochem. Soc. Trans., 2008, 36, 1293-1298.
[61] Hilgert, M.; Nöldner, M.; Chatterjee, S.S.; Klein, J. KA-672 inhibits rat brain [84] Zecca, L.; Youdim, M.B.H.; Riederer, P.; Connor J.R.; Crichton, R.R. Iron,
acetylcholinesterase in vitro but not in vivo. Neurosci. Lett., 1999, 263, 193- brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci., 2004, 5,
196. 863-873.
[62] Gnerre, C.; Catto, M.; Leonetti, F.; Weber, P.; Carrupt, P.A.; Altomare, C.; [85] Zheng, H.; Weiner, L.M.; Bar-Am, O.; Epsztejn, S.; Cabantchik, Z.I.;
Carotti, A.; Testa, B. Inhibition of monoamine oxidases by functionalized Warshawsky, A.; Youdim, M.B.H.; Fridkin, M. Design, synthesis, and
coumarin derivatives: biological activities, QSARs, and 3D-QSARs. J. Med. evaluation of novel bifunctional iron-chelators as potential agents for
Chem., 2000, 43, 4747-4758. neuroprotection in Alzheimer’s, Parkinson’s, and other neurodegenerative
[63] Bruhlmann, C.; Ooms, F.; Carrupt, P.A.; Testa, B.; Catto, M.; Leonetti, F.; diseases. Bioorg. Med. Chem., 2005, 13, 773-783.
Altomare, C.; Carotti, A. Coumarins derivatives as dual inhibitors of [86] Ben Shachar, D.B.; Kahana, N.; Kampel, V.; Warshawsky, A.; Youdim,
acetylcholinesterase and monoamine oxidase. J. Med. Chem., 2001, 44, M.B.H. Neuroprotection by a novel brain permeable iron chelator, VK-28,
3195-3198. against 6-hydroxydopamine lesion in rats. Neuropharmacology, 2004, 46,
[64] Pisani, L.; Catto, M.; Giangreco, I.; Leonetti, F.; Nicolotti, O.; Stefanachi, 254-263.
A.; Cellamare, S.; Carotti, A. Design, synthesis and biological evaluation of [87] Zheng, H.; Gal, S.; Weiner, L.M.; Bar-Am, O.; Warshawsky, A.; Fridkin,
coumarin derivatives tethered to an edrophonium-like fragment as highly M.; Youdim, M.B.H. Novel multifunctional neuroprotective iron chelator-
4586 Current Medicinal Chemistry, 2011 Vol. 18, No. 30 Pisani et al.
monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro by p53 pathway inhibition in MPP+-treated SH-SY5Y human dopaminergic
studies on antioxidant activity, prevention of lipid peroxide formation and cells. J. Neurochem., 2008, 105, 2404-2417.
monoamine oxidase inhibition. J. Neurochem., 2005, 95, 68-78. [105] Battaglia, V.; Sanz, E.; Salvi, M.; Unzeta, M.; Toninello, A. Protective effect
[88] Youdim, M.B.H.; Fridkin, M.; Zheng, H. Bifunctional drug derivatives of of N-(2-propynyl)-2-(5-benzyloxy-indolyl)methylamine (PF9601N) on
MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective mitochondrial permeability transition. Cell. Mol. Life Sci., 2006, 63, 1440-
approach to treatment of brain ageing and ageing neurodegenerative diseases. 1448.
Mech. Ageing Dev., 2005, 126, 317-326. [106] Bellik, L.; Dragoni, S.; Pessina, F.; Sanz, E.; Unzeta, M.; Valoti, M.
[89] a) Tatton, W.; Chalmers-Redman, R.; Tatton, N. Neuroprotection by Antioxidant properties of PF9601N, a novel MAO-B inhibitor: assessment of
deprenyl and other propargylamines: glyceraldehyde-3-phosphate its ability to interact with reactive nitrose species. Acta Biochim. Pol., 2010,
dehydrogenase rather than monoamine oxidase B. J. Neural Transm., 2003, 57, 235-239.
110, 509-515; b) Maruyama, W.; Youdim, M.B.H.; Naoi, M. Antiapoptotic [107] Prins, L.H.A.; Petzer, J.P.; Malan, S.F. Synthesis and in vitro evaluation of
properties of rasagiline, N-propargylamine-1(R)-aminoindan, and its optical pteridine analogues as monoamine oxidase B and nitric oxide synthase
(S)-isomer, TV1022. Ann. N. Y. Acad. Sci., 2001, 939, 320-329. inhibitors. Bioorg. Med. Chem., 2009, 17, 7523-7530.
[90] Avramovich-Tirosh, Y.; Amit, T.; Bar-Am, O.; Zheng, H.; Fridkin, M.; [108] Xu, K.Y.; Huso, D.L.; Dawson, T.M.; Bredt, D.S.; Becker, L.C. Nitric oxide
Youdim, M.B.H. Therapeutic targets and potential of the novel brain- synthase in cardiac sarcoplasmic reticulum. Proc. Natl. Acad. Sci. USA,
permeable multifunctional iron chelator-monoamine oxidase inhibitor drug, 1999, 96, 657-662.
M-30, for the treatment of Alzheimer's disease. J. Neurochem., 2007, 100, [109] Herraiz, T.; Aran, V. J.; Guillen, H. Nitroindazole compounds inhibit the
490-502. oxidative activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
[91] Zheng, H.; Youdim, M.B.H.; Fridkin, M. Site-activated chelators targeting (MPTP) neurotoxin to neurotoxic pyridinium cations by human monoamine
acetylcholinesterase and monoamine oxidase for Alzheimer’s therapy. ACS oxidase (MAO). Free Radical Res., 2009, 43, 975-984.
Chem. Biol., 2010, 5, 603-610. [110] Castagnoli, K.; Palmer, S.; Anderson, A.; Bueters, T.; Castagnoli, N.Jr. The
[92] Lee, M.H.; Lin, R.D.; Shen, L.Y.; Yang, L.L.; Yen, K.Y.; Hou, W.C. neuronal nitric oxide synthase inhibitor 7-nitroindazole also inhibits the
Monoamine oxidase B and free radical scavenging activities of natural monoamine oxidase-B-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-
flavonoids in melastoma candidum D. Don. J. Agric. Food Chem., 2001, 49, tetrahydropyridine. Chem. Res. Toxicol., 1997, 10, 364-368.
5551-5555. [111] Thomas, B.; Saravanan, K.S.; Mohanakumar, K.P. In vitro and in vivo
[93] Chimenti, F.; Cottiglia, F.; Bonsignore, L.; Casu, L.; Casu, M.; Floris, C.; evidences that antioxidant action contributes to the neuroprotective effects of
Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; Befani, O.; Turini, P.; the neuronal nitric oxide synthase and monoamine oxidase-B inhibitor, 7-
Alcaro, S.; Ortuso, F.; Trombetta, G.; Loizzo, A.; Guarino, I. Quercetin as nitroindazole. Neurochem. Int., 2008, 52, 990-1001.
the active principle of Hypericum hircinum exerts a selective inhibitory [112] Babbedge, R.C.; Bland-Ward, P.A.; Hart, S.L.; Moore, P.K. Inhibition of rat
activity against MAO-A: Extraction, biological analysis, and computational cerebellar nitric oxide synthase by 7-nitroindazole and related substituted
study. J. Nat. Prod., 2006, 69, 945–949. indazoles. Br. J. Pharmacol., 1993, 110, 225-228.
[94] Herraiz, T.; Guillén, H. Inhibition of the bioactivation of the neurotoxin [113] Doraiswamy, P.M. Non-cholinergic strategies for treating and preventing
MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Alzheimer's disease. CNS Drugs, 2002, 16, 811-824.
Food Chem. Toxicol., 2011, 49, 1773-1781. [114] Marx, J. Neurodegenerative disease: searching for drugs that combat
[95] Ogata, M.; Hoshi, M.; Urano, S.; Endo, T. Antioxidant activity of eugenol Alzheimer's. Science, 1996, 273, 50.
and related monomeric and dimeric compounds. Chem. Pharm. Bull., 2000, [115] Pasinetti, G.M. From epidemiology to therapeutic trials with anti-
48, 1467-1469. inflammatory drugs in Alzheimer's disease: the role of NSAIDs and
[96] Tao, G.; Irie, Y.; Li, D.J.; Keung, W.M. Eugenol and its structural analogs cyclooxygenase in beta-amyloidosis and clinical dementia. J. Alzheimer’s
inhibit monoamine oxidase A and exhibit antidepressant-like activity. Dis., 2002, 4, 435-445.
Bioorg. Med. Chem., 2005, 13, 4777-4788. [116] Aisen, P.S.; Schafer, K.A.; Grundman, M.; Pfeiffer, E.; Sano, M.; Davis,
[97] Moncada, S.; Palmer, R.M.J.; Higgs, E.A. Nitric oxide: physiology, K.L.; Farlow, M.R.; Jin, S.; Thomas, R.G.; Thal, L.J. Effects of rofecoxib or
pathophysiology, and pharmacology. Pharmacol. Rev., 1991, 43, 109-142. naproxen vs placebo on Alzheimer disease progression: a randomized
[98] Misra, M.K.; Sarwat, M.; Bhakuni, P.; Tuteja, R.; Tuteja, N. Oxidative stress controlled trial. JAMA, 2003, 289, 2819-2826.
and ischemic myocardial syndromes. Med. Sci. Monit., 2009, 15, RA209- [117] Gökhan-Kelekçi, N.; Yabanolu, S.; Küpeli, E.; Salgın, U.; Özgen, Ö.; Uçar,
219. G.; Yeilada, E.; Kendi, E.; Yeilada, A.; Bilgin, A.A. A new therapeutic
[99] a) Novo, E.; Parola, M. Redox mechanisms in hepatic chronic wound healing approach in Alzheimer disease: Some novel pyrazole derivatives as dual
and fibrogenesis. Fibrogenesis Tissue Repair, 2008, 1, 5; b) Brzozowski, MAO-B inhibitors and anti-inflammatory analgesics. Bioorg. Med. Chem.,
M.J.; Alcantara, S.L.; Iravani, M.M.; Rose, S.; Jenner, P. The effect of nNOS 2007, 15, 5775-5786.
inhibitors on toxin-induced cell death in dopaminergic cell lines depends on [118] Guigoni, C.; Aubert, I.; Li, Q.; Gurevich, V.V.; Benovic, J.L.; Ferry, S.;
the extent of enzyme expression. Brain Res., 2011, 1404, 21-30; c) Beckman, Mach, U.; Stark, H.; Leriche, L.; Håkansson, K.; Bioulac, B.H.; Gross, C.E.;
J.S.; Koppenol, W.H. Nitric oxide, superoxide, and peroxynitrite: the good, Sokoloff, P.; Fisone, G.; Gurevich, E.V.; Bloch, B.; Bezard, E. Pathogenesis
the bad, and ugly. Am. J. Physiol., 1996, 271, C1424-1437. of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors.
[100] Tuteja, N.; Chandra, M.; Tuteja, R.; Misra, M.K. Nitric oxide as a unique Parkinsonism Relat. D., 2005, 1, S25-S29.
bioactive signaling messenger in physiology and pathophysiology. J. [119] Chen, J.F.; Xu, K.; Petzer, J.P.; Staal, R.; Xu, Y.H.; Beilstein, M.; Sonsalla,
Biomed. Biotech., 2004, 4, 227-237. P.K.; Castagnoli, K.; Castagnoli, N.Jr.; Schwarzschild, M.A.
[101] Silverman, R.B. Design of selective neuronal nitric oxide synthase inhibitors Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a
for the prevention and treatment of neurodegenerative diseases. Acc. Chem. model of Parkinson's disease. J. Neurosci., 2001, 21, RC143.
Res., 2009, 42, 439-451. [120] Bibbiani, F.; Oh, J.D.; Petzer, J.P.; Castagnoli, N.Jr.; Chen, J.F.;
[102] a) Cruces, M.A.; Elorriaga, C.; Fernandez-Alvarez, E.; Lopez Chico, M.T.; Schwarzschild, M.A.; Chase, T.N. A 2A antagonist prevents dopamine
Nieto Lopez, O. Acetylenic and allenic derivatives of 2-(1- agonist-induced motor complications in animal models of Parkinson's
methylindolyl)methylamine as selective inhibitors of the monoamine disease. Exp. Neurol., 2003, 184, 285-294.
oxidases A and B. Farmaco Sci., 1988, 43, 567-573; b) Cruces, M.A.; [121] a) Schwarzschild, M.A.; Agnati, L.; Fuxe, K.; Chen, J.F.; Morelli, M.
Elorriaga, C.; Fernandez-Alvarez, E. Acetylenic and allenic derivatives of 2- Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci.,
(5-methoxyindolyl) and 2-(5-hydroxyindolyl)methylamines: synthesis and in 2006, 29, 647-654; b) Xu, K.; Bastia, E.; Schwarzschild, M. Therapeutic
vitro evaluation as monoamine oxidase inhibitors. Eur. J. Med. Chem., 1991, potential of adenosine A(2A) receptor antagonists in Parkinson's disease.
26, 33-41; c) Avila, M.; Balsa, M.D.; Fernandez-Alvarez, E.; Tipton, K. F.; Pharmacol. Ther., 2005, 105, 267-310.
Unzeta, M. The effect of side-chain substitution at positions 2 and 3 of the [122] a) Saura, J.; Richards, J.G.; Mahy, N. Differential age-related changes of
heterocyclic ring of N-acetylenic analogues of tryptamine as monoamine MAO-A and MAO-B in mouse brain and peripheral organs. Neurobiol.
oxidase inhibitors. Biochem. Pharmacol., 1993, 45, 2231-2237; d) Balsa, D.; Aging, 1994, 15, 399-408; b) Fowler, J.S.; Volkow, N.D.; Wang, G.-J.;
Fernandez-Alvarez, E.; Tipton, K.F.; Unzeta, M. Monoamine oxidase Logan, J.; Pappas, N.; Shea, C.; Macgregor, R. Age-related increases in brain
inhibitory potencies and selectivities of 2-[N-(2-propynyl)-aminomethyl]-1- monoamine oxidase B in living healthy human subjects. Neurobiol. Aging,
methyl indole derivatives. Biochem. Soc. Trans., 1991, 19, 215-218. 1997, 18, 431-435.
[103] Perez, V.; Marco, J.L.; Fernandez-Alvarez, E.; Unzeta, M. Relevance of a [123] Jacobson, K.A.; Gallo-Rodriguez, C.; Melman, N.; Fischer, B.; Maillard, M.;
benzyloxy group in 2-indolyl methylamines in the selective MAO-B van Bergen, A.; van Galen, P.J.; Karton, Y. Structure-activity relationships
inhibition. Br. J. Pharmacol., 1999, 127, 869-876. of 8-styrylxanthines as A2-selective adenosine antagonists. J. Med. Chem.,
[104] a) Perez, V.; Unzeta, M. PF9601N [N-(2-propynyl)-2-(5-benzyloxyindolyl) 1993, 36, 1333-1342.
methylamine], a new MAO-B inhibitor, attenuates MPTP induced depletion [124] Chen, J.F.; Steyn, S.; Staal, R.; Petzer, J.P.; Xu, K.; Van Der Schyf, C.J.;
of striatal dopamine levels in C57/BL mice. Neurochem. Intern., 2003, 42, Castagnoli, K.; Sonsalla, P.K.; Castagnoli, N.Jr.; Schwarzschild, M.A. 8-(3-
221-229; b) Cutillas, B.; Ambrosio, S.; Unzeta, M. Neuroprotective effect of Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual
the monoamine oxidase inhibitor PF9601N [N-(2-propynyl)-2-(5-benzyloxy- actions of monoamine oxidase inhibition and A2A receptor antagonism. J.
indolyl) methylamine] on rat nigral neurons after 6-OH-DA striatal Biol. Chem., 2002, 277, 36040-36044.
lesion. Neurosci. Lett., 2002, 329, 165-168; c) Sanz, E.; Quintana, A.; [125] Petzer, J.P.; Steyn, S.; Castagnoli, K.P.; Chen, J.F.; Schwarzschild, M.A.;
Battaglia, V.; Toninello, A.; Hidalgo, J.; Ambrosio, S.; Valoti, M.; Marco, Van der Schyf, C.J.; Castagnoli, N. Inhibition of monoamine oxidase B by
J.L.; Tipton, K.F.; Unzeta, M. Anti-apoptotic effect of MAO-B inhibitor selective adenosine A2A receptor antagonists. Bioorg. Med. Chem., 2003, 11,
PF9601N [N-(2-propynyl)-2-(5-benzyloxyindolyl)methylamine] is mediated 1299-1310.
Targeting Monoamine Oxidases with Multipotent Ligands Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4587
[126] Pretorius, J.; Malan, S.F.; Castagnoli, N.Jr.; Bergh, J.J.; Petzer, J.P. Dual inhibition and structure of the human monoamine oxidase B complex. J.
inhibition of monoamine oxidase B and antagonism of the adenosine A2A Med. Chem., 2011, 54, 909-912.
receptor by (E,E)-8-(4-phenylbutadien-1-yl)caffeine analogues. Bioorg. Med. [136] Heneka, M.T.; Sastre, M.; Dumitrescu-Ozimek, L.; Hanke, A.; Dewachter, I.;
Chem., 2008, 16, 8676-8684. Kuiperi, C.; O'Banion, K.; Klockgether, T.; Van Leuven, F.; Landreth, G.E.
[127] a) Hung, A.Y.; Haass, C.; Nitsch, R.M.; Qiu, W.Q.; Citron, M.; Wurtman, Acute treatment with the PPARg agonist pioglitazone and ibuprofen reduces
R.J.; Growdon, J.H.; Selkoe, D.J. Activation of protein kinase C inhibits glial inflammation and Ab 1–42 levels in APPV7171 transgenic mice. Brain,
cellular production of the amyloid beta-protein. J. Biol. Chem., 1993, 268, 2005, 128, 1442-1453.
22959–22962; b) Bandyopadhyay, S.; Goldstein, L.E.; Lahiri, D.K.; Rogers, [137] Breidert, T.; Callebert, J.; Heneka, M.T.; Landreth, G.; Launay, J.M.; Hirsch,
J.T. Role of the APP non-amyloidogenic signaling pathway and targeting E.C. Protective action of the peroxisome proliferator-activated receptor-
alpha-secretase as an alternative drug target for treatment of Alzheimer's agonist pioglitazone in a mouse model of Parkinson’s disease. J.
disease. Curr. Med. Chem., 2007, 14, 2848-2864; c) Bar-Am, O.; Amit, T.; Neurochem., 2002, 82, 615-624.
Weinreb, O.; Youdim, M.B.H.; Mandel, S. Propargylamine containing [138] Dehmer, T.; Heneka, M.T.; Sastre, M.; Dichgans, J.; Schultz, J.B. Protection
compounds as modulators of proteolytic cleavage of amyloid-beta protein by pioglitazone in the MPTP model of Parkinson’s disease correlates with
precursor: involvement of MAPK and PKC activation. J. Alzheimer’s Dis., IkBa induction and block of NFkB and iNOS activation. J. Neurochem.,
2010, 21, 361-371. 2004, 88, 494-501.
[128] Yogev-Falach, M.; Amit, T.; Bar-Am, O.; Weinstock, M.; Youdim, M.B.H. [139] Quinn, L.P.; Crook, B.; Hows, M.E.; Vidgeon-Hart, M.; Chapman, H.;
Involvement of MAP kinase in the regulation of amyloid precursor protein Upton, N.; Medhurst, A.D.; Virley, D.J. The PPAR agonist pioglitazone is
processing by novel cholinesterase inhibitors derived from rasagiline. FASEB effective in the MPTP mouse model of Parkinson’s disease through
J., 2002, 16, 1674–1676. inhibition of monoamine oxidase B. Br. J. Pharmacol., 2008, 154, 226-233.
[129] Hu, M.K.; Liao, Y.F.; Chen, J.F.; Wang, B.J.; Tung, Y.T.; Lin, H.C.; Lee, [140] a) Combs, C.K.; Johnson, D.E.; Karlo, J.C.; Cannady, S.B.; Landreth, G.E.
K.P. New 1,2,3,4-tetrahydroisoquinoline derivatives as modulators of Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-
proteolytic cleavage of amyloid precursor proteins. Bioorg. Med. Chem., amyloid-stimulated proinflammatory responses and neurotoxicity by
2008, 16, 1957-1965. PPARgamma agonists. J. Neurosci., 2000, 2, 558-567; b) Inestrosa, N.C.;
[130] Murata, M.; Hasegawa, K.; Kanazawa, I.; Murata, M.; Hasegawa, K.; Godoy, J.A.; Quintanilla, R.A.; Koenig, C.S.; Bronfman, M. Peroxisome
Kanazawa, I. The Japan Zonisamide on, P. D. S. G. Zonisamide improves proliferator-activated receptor gamma is expressed in hippocampal neurons
motor function in Parkinson disease: a randomized, double-blind study. and its activation prevents beta-amyloid neurodegeneration: role of Wnt
Neurology, 2007, 68, 45-50. signalling. Exp. Cell Res., 2005, 304, 91-104.
[131] Biton, V. Clinical pharmacology and mechanism of action of zonisamide. [141] Recent advances in QSAR studies. Methods and applications. In: Challenges
Clin. Neuropharmacol., 2007, 30, 230-240. and Advances in Computational Chemistry and Physics, 1st ed., vol. 8.;
[132] Asanuma, M.; Miyazaki, I. Protective effects of a novel anti-parkinsonian Puzyn, T.; Leszczynski, J.; Cronin, M.T.D. Eds.; Springer: Dordrecht, The
agent zonisamide on dopamine quinone-related neurotoxicity. Society for Netherlands, 2010.
Neuroscience Program Nol 158, 2007, 1. [142] a) 3D QSAR in drug design: recent advances. In: Perspectives in drug
[133] Tokumaru, J.; Ueda, Y.; Yokoyama, H.; Nakajima, A.; Doi, T.; Mitsuyama, discovery and design, vol. 12-14; Kubinyi, H.; Folkers, G.; Martin, Y.C.
Y.; Ohya-Nishiguchi, H.; Kamada, H. In vivo evaluation of hippocampal Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1998; b) 3D
anti-oxidant ability of zonisamide in rats. Neurochem. Res., 2000, 25, 1107- QSAR in drug design: ligand-protein interactions and molecular similarity,
1111. vol. 2; Kubinyi, H.; Folkers, G.; Martin, Y.C. Eds.; Kluwer Academic
[134] Sonsalla, P. K.; Wong, L.-Y.; Winnik, B.; Buckley, B. The antiepileptic drug Publishers: Dordrecht, The Netherlands, 1998.
zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: Clinical [143] Pharmacophores and Pharmacophore Searches. In: Methods and Principles
relevance. Exp. Neurol., 2010, 221, 329-334. in Medicinal Chemistry, vol. 32, Langer, T.; Hoffmann, R.D. Eds.; Wiley-
[135] Binda, C.; Aldeco, M.; Mattevi, A.; Edmondson, D.E. Interactions of VCH: New York, 2006.
monoamine oxidases with the antiepileptic drug zonisamide: Specificity of
Received: May 20, 2011 Revised: August 05, 2011 Accepted: August 08, 2011