Kumar 2021

Reviews
ChemMedChem doi.org/10.1002/cmdc.202100045
Piperazine, a Key Substructure for Antidepressants: Its Role

in Developments and Structure-Activity Relationships
Ravi Ranjan Kumar,[a] Bhaskar Sahu,[a] Shelly Pathania,[a] Pankaj Kumar Singh,[b]
M. Jawaid Akhtar,[a] and Bhupinder Kumar*[a]
Depression is the single largest contributor to global disability of the significance of the piperazine moiety in the development
with a huge economic and social burden on the world. There of antidepressants has been performed. An overview of current
are a number of antidepressant drugs on the market, but developments in the designing and synthesis of piperazine-
treatment-resistant depression and relapse of depression in a based antidepressants (2015 onwards) along with SAR studies is
large number of patients have increased problems for clinicians. also provided. The various piperazine-based therapeutic agents
One peculiarity observed in most of the marketed antidepres- in early- or late-phase human testing for depression are also
sants is the presence of a piperazine substructure. Although discussed. The preclinical compounds discussed in this review
piperazine is also used in the optimization of other pharmaco- will help researchers understand how piperazine actually
logical agents, it is almost extensively used for the development influences the design and development of novel antidepressant
of novel antidepressants. One common understanding is that compounds. The SAR studies discussed will provide crucial clues
this is due to its favorable CNS pharmacokinetic profile; about the structural features and optimizations required to
however, in the case of antidepressants, piperazine plays a enhance the efficacy and potency of piperazine-based anti-
much bigger role and is involved in specific binding conforma- depressants.
tions of these agents. Therefore, in this review, a critical analysis
1. Introduction sants selectively inhibit the reuptake of serotonin through its

receptors thereby increasing its concentration around the
Depression is the most common cause of emotional suffering nerves in the brain.[10] Currently, selective serotonin reuptake
related to a decrease in quality of life in the older population.[1,2] inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhib-
But, recently the prevalence of depression in young adults and itors (SNRIs) are first-line treatment for major depressive
adolescents has increased sharply.[3] According to an estimate, disorders[11–12] which inhibit the reuptake of serotonin (5-HT)
around 300 million people are affected by major depressive and norepinephrine (NE) released from nerve cells in the brain.
disorder (MDD).[4] One in every five women and one in every Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepres-
eight men has experienced MDD at some time in their life.[5] sants (TCAs) are also an important class of antidepressants but
Depression is also a leading cause of suicidal deaths in the are mostly used as second-line drugs.[13,14] MAOIs inhibit the
world.[6,7] It can also cause cognitive impairment and social MAO enzyme, thereby inhibiting the oxidative metabolism of
dysfunction with heavy distress.[8] The global market for drugs monoamine neurotransmitters,[15] whereas TCAs prevent the
used in depression is expected to be around $13 billion.[9] reuptake of acetylcholine along with 5-HT and NE in the nerve
Mechanistically, the action of antidepressant drugs is mono- cells.[16,17]
aminergic, which mainly involves two neurotransmitters, seroto- In most antidepressant drugs, piperazine is a common
nin and noradrenaline. structural moiety which indicates its importance in these CNS
Physiologically, serotonin binds to the specific site of 5-HT active agents.[18,19] Piperazine is a six-membered heterocyclic
receptor present outside of the cell and induces subtle changes molecule with two nitrogen atoms present diagonally to each
in the shape of the protein and sends a signal to G proteins other.[20–22] Piperazine core is well-known to play an important
inside the cell, leading to an excitatory response in the cells, role in balancing the pharmacokinetic profile of designed
and in other cases results in inhibitory response. Out of the two, compounds. Due to this innate quality, since long it has been
more attention has been given to serotonin, the antidepres- used in the development of various classes of pharmacologi-
cally active compounds including anthelmintic,[23] antioxidant,[24]
[a] R. R. Kumar, B. Sahu, S. Pathania, Dr. M. J. Akhtar, Dr. B. Kumar antimicrobial,[25,26] anti-HIV,[27,28] antiviral,[29,30] anti-
[31,32] [33]
Department of Pharmaceutical Chemistry inflammatory, cognition enhancer, metal chelators,[34]
ISF College of Pharmacy anti-Parkinson’s,[35] antidiabetic,[36] antimalarial,[37,38]
Ghal Kalan, G.T Road, Moga, Punjab, 142001 (India) [39,40] [41–43]
E-mail: bhupinderkumar@isfcp.org antidepressant, anti-Alzheimer’s, antitubercular,[44]
[45]
[b] Dr. P. K. Singh antiplasmodial, etc. There are several drug molecules in
Integrative Physiology and Pharmacology clinical use which contain piperazine pharmacophore in its
Institute of Biomedicine, Faculty of Medicine
University of Turku structural features (Table 1). However, in the case of antidepres-
20520 Turku (Finland) sants, it has been reported to play a more crucial role, whereby
ChemMedChem 2021, 16, 1 – 25 1 © 2021 Wiley-VCH GmbH
These are not the final page numbers! ��

Reviews
it interacts with vital binding pocket residues and increases the 1.1. Role of piperazine in antidepressant agents: Binding
affinity of the designed compounds. As a synthon, piperazine mode analysis of clinical drugs
provides wide opportunities for modification and designing of
new molecules with improved antidepressant activity and Till date there are several piperazine containing molecules
pharmacokinetic profile including other CNS activities.[20,46] approved for the management of clinical depression (Table 1).
Although there are some reports published on ongoing Mechanistically, almost all of them act as agonist (partial/full) of
developments of piperazine-based therapeutic serotonin receptor (5-HT1 A). Interestingly, close inspection of
targets.[18,19,23,47–49] the current work provides critical understand- their structural framework reveals, that most of piperazine-
ing of the role of piperazine scaffold in the current work on based FDA-approved antidepressants have presence of piper-
antidepressants (2015 onwards) along with their SAR studies. azine as a bridge between the two aromatic/heteroaromatic
This review also focuses on various piperazine-based therapeu- flanks.[50] A general binding conformations of different FDA-
tic agents in early or late phase human testing for depression approved antidepressants in the binding pocket of 5-HT1 A
currently. For an in-depth review of antidepressant develop- have certain common features including, a salt-bridge with
ments under progress, the researchers are directed to several Asp116, CH–π/π–π interactions side chains of Phe361 and π–π
studies. stacking interactions with Phe362 {Kucwaj-Brysz, 2018 #2775}.
However certain interactions are peculiar to specific molecule
including hydrogen bond interactions with Cys187, Ser199 and
Asn386. Further, detailed analysis of their bound conformation
focussing on piperazine in the catalytic domain of serotonin
receptor disclosed that nitrogen atom of piperazine protonates
at the physiological pH and forms a key salt bridge interaction
Ravi Ranjan Kumar is pursuing an M. Pharm in Pankaj Kumar Singh received his Ph.D. in
pharmaceutical chemistry at ISF college of medicinal chemistry from Punjabi University,
Pharmacy, Moga under the supervision of Dr. Patiala in 2019. In 2020, he was appointed as
Bhupinder Kumar. He is working on the design TCSMT post-doctoral fellow at the Institute of
and synthesis of substituted piperazine deriv- Biomedicine, University of Turku. From 2019–
ative and their screening as antidepressant 2020, he worked as a research fellow at the
agents. He completed the Bachelor’s of Phar- University of Sassari. His specialization is in
macy at ISF college of Pharmacy, Moga in computational and experimental medicinal
2019 and is twice GPAT qualified (2019, 2020). chemistry. His research mainly includes devel-
oping small-molecule inhibitors for epigenetic
Bhaskar Sahu is pursuing an M. Pharm in targets, ROS modulators, Photo-affinity la-
pharmaceutical chemistry at ISF college of belled ligands, kinase inhibitors, anti-tubercu-
Pharmacy, Moga under the supervision of Dr. lar agents etc.
Bhupinder Kumar. He is working on the design
Md Jawaid Akhtar is currently working as
and synthesis of substituted piperazine deriv-
Assistant Professor at the Deptartment of
ative and their screening as antidepressant
Pharmaceutical Chemistry, College of Phar-
agents. He completed the Bachelor’s of Phar-
macy, National University of Science and
macy at ISF college of Pharmacy, Moga in
Technology, Muscat, Sultanate of Oman. He
2019 and qualified GPAT in 2019.
obtained M. Pharm. and Ph.D. degrees in
pharmaceutical chemistry from the School of
Shelly Pathania has been an Assistant Profes-
Pharmaceutical Education and Research, Jamia
sor in the Department of Pharmaceutical
Hamdard University, New Delhi, India. His area
Chemistry, ISF College of Pharmacy, Moga,
of research interests are computer-aided drug
since 2016. Her research project involves using
design (CADD) and synthesis of heterocyclic
in silico techniques to target MAPK/ERK signal-
compounds of medicinal importance.
ing pathway for the management of breast
cancer. She has approximately six years of Bhupinder Kumar is an Associate Professor at
experience in teaching and research. Her the Department for Pharmaceutical Chemistry
research mainly includes molecular modelling- and Analysis of ISF College of Pharmacy,
based development of new lead molecules for Moga, Punjab. He completed his PhD in
anti-inflammatory, anticonvulsant, antiviral pharmaceutical chemistry at the Central Uni-
and anticancer targets. versity of Punjab, Bathinda. He is University
Gold medal recipient for his outstanding
academic and research performance in M.
Pharm. His research interests are in medicinal,
organic, analytical and green chemistry. His
expertise includes drug designing and syn-
thesis, green synthesis and analytical method
development.
ChemMedChem 2021, 16, 1 – 25 www.chemmedchem.org 2 © 2021 Wiley-VCH GmbH

Reviews
Table 1. Various piperazine-based drugs on the market.

Drug Name Structure Mechanism of action Development/appro- Ref.
val year
amoxapine serotonin reuptake inhibitor (SERT), 5-HT1A partial agonist 1992 [54]
serotonin reuptake inhibitor (SERT), norepinephrine reuptake

Befuraline 1970 s [55]
inhibitor (NET)
Buspirone 5-HT1A agonist 1986 [56]
serotonin reuptake inhibitor (SERT), norepinephrine reuptake

Piberaline 1980 s [57]
inhibitor (NET)
Nefazodone 5-HT1AR agonist and 5-HT2R antagonist 1994 [58]
Tandospirone agonist of the 5-HT1A receptor 1990 s [59]
Trazodone 5-HT1AR agonist and 5-HT2R antagonist 1981 [60]
Vilazodone agonist of the 5-HT1A receptor 2011 [61]
serotonin reuptake inhibitor (SERT), 5-HT1AR partial agonist,

Vortioxetine 2017 [62]
5-HT3R agonist
with Asp116 of the catalytic domain of 5HT1 A[51,52] (Figure 1). Vortioxetine has terminal piperazine and accordingly it fails to
Along with other key interactions, this crucial contact stabilizes interact with Asp116. This information re-emphasises the addi-
the complex of these therapeutic agents with the target.[53] It tional significance of the piperazine derivatives in the develop-
also improves the binding affinity between the serotonin ment of antidepressants.
receptor and the piperazine bridge containing molecules. This
key interaction also explains why piperazine moiety, a conven-
tionally terminally attached moiety, is placed in the centre of
these molecules. Out of all the molecules considered for the
binding mode analysis, five (befuraline, buspirone, piberaline,
tandospirone and trazodone) have piperazine in between and
all of them form key interaction with Asp116 while only

Reviews
D2 receptor as compared to Fananserin. This compound was

selected as lead for the development of compounds with high
affinity for 5-HT1A,5-HT7, and D2 receptor. The SAR studies
revealed that with the increase in alkyl chain up to six carbons
and a fluorine substituent at the 2nd/3rd position in the
arylpiperazine leads to an increase in affinity for 5-HT1A and D2
receptor (Figure 1). The replacement of fluorine substituent
with a larger halogen (Cl, CF3) group leads to a decrease in
affinity towards 5-HT1A and D2 receptors. Further, the replace-
ment of sultam to lactam group caused a decrease in affinity
towards all receptors except 5-HT1A. Docking analysis disclosed
that these compounds were able to form a hydrogen bond
between the nitrogen present in arylpiperazine ring and
carboxylic group of Asp106 (salt bridge 3.0–3.1 Å).
Zagorska et al. synthesized a series of novel 2-fluoro and 3-
Figure 1. Binding mode of various FDA-approved piperazine-based antide- trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imida-
pressants highlighting the role of piperazine moiety. zo[2,1-f]purine-2,4(3H,8H)-dione as a potential antidepressant
agents and phosphodiesterase inhibitors (PDE4B and
PDE10 A).[64] The antidepressant activity of synthesized deriva-
tives was evaluated in vivo and in vitro (5-HT1 and 5-HT7
2. Recent Advancements in Piperazine receptors). The results from preliminary in vivo forced swim test
Derivatives as Antidepressants (FST) studies revealed that compound 4, 8-(5-(4-(2-fluorophen-
yl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-
Zareba et al. synthesized a series of new bulky Fananserin 2,4(3H,8H)-dione, possesses most potent antidepressant activity
derivatives and evaluated their antidepressant potential.[63] The in mice. Similarly, in antianxiety studies, compound 4 (2.5 mg/
designed hits were obtained from SAR studies for LCAP (long- kg) showed a promising profile with greater effect than the
chain arylpiperazine derivatives) reported in the literature and reference drug diazepam. The potent compounds were further
virtual screening. In this series, a total of 18 new derivatives subjected to in vitro studies against 5-HT1A and 5-HT7 receptors
were synthesized and evaluated for their antidepressant activity where compound 4 (Figure 3) showed a significant affinity for
against various isoforms of serotonin and dopamine receptors 5-HT1A with Ki values of 2.5 � 0.2 and 30.8 � 3.5 nM respectively.
(5-HT1A,5-HT7, and D2). The result from in vitro studies revealed In these studies, compound 5 (Figure 2) was found to possess
that compound 1 (Figure 2) possesses a higher affinity towards the most potent Ki against 5-HT1A of 0.1 � 0.02 nM. The potent
compounds were also subjected to PDE4B and PDE10 A
inhibition studies where these showed low to moderate
inhibition. SAR studies revealed that long-chain arylpiperazine
derivatives having imidazo[2,1-f]purine-2,4-dione moiety, a
spacer of four carbons, and 3-CF3 substitution at aryl moiety
possess most potent 5-HT1A antagonist activity. The increase of
spacer chain from four carbons to five lead to decrease in the
activity. Further, to understand the binding mode of compound
4 at 5-HT1A and 5-HT7 receptors, molecular docking studies were
performed. The results from these in silico studies revealed that
fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]
purine-2,4(3H,8H)-dione play a key role in interactions at the
active site of both 5-HT1A and 5-HT7 receptors. The docking
studies also showed that there are two cavities in both receptor
models from which one is between transmembrane helices
(TMHs) 3 and 6 for both and the second is between THMs 2 and
7 for 5HT1A or THMs 3 and 7 for 5HT7 receptor. The major
interactions found were hydrogen bonding between the nitro-
gen atom of arylpiperazine and carboxylic group of Asp3.32
and CH–π interaction between arylpiperazine and aromatic
amino acid of the active site cavity.
The same research group synthesized a series of novel 2-
pyrimidynyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]
purine-2,4(3H,8H)-dione as CNS active agents.[65] Among the
Figure 2. Piperazine-based fananserin derivatives as antidepressants. synthesized compounds, most of them showed a potent affinity

Reviews
Figure 3. Piperazine-based 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as antidepressants.
towards 5HT1ARs with Ki ranging from 2.2 to 20 nM. The results by forming charge-reinforced H-bond with Asp3.32 and CH–π
from in vitro studies revealed that compound 6, 2-pyrimidinyl-1- aromatic stacking with Phe6.52. Further, in vivo studies revealed
piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione, possess a po- that compound 6 possesses metabolic stability in mouse liver
tent selective antagonistic effect against 5-HT1A receptor which microsomes and low first-pass effect. From PAMPA studies, it
play a vital role in depression. These compounds were further was observed that 6 has a low binding affinity to plasma
subjected to determine their binding affinity towards 5HT7. proteins and high intestinal absorption.
From these studies, it was found that except compound 7, all Gu et al. designed and synthesized a series of arylalkanol
compounds were inactive towards 5HT7 receptors. SAR studies and aralkyl piperazine derivatives as potential antidepressant
confirmed that spacer length of four carbons between the compounds.[66] In this series, they synthesized a total of 16
purine core and 2-pyrimidinyl-1-piperazinyl moiety is most compounds and evaluated for their serotonin reuptake inhib-
suitable for potent antidepressant activity. In the presence of itory activities (RUI) along with 5-HT1A and 5-HT7 receptors
optimum carbon spacer, substitution at seventh position of affinities activity. Out of all, compound 8 (Figure 4) possessed
purine core did not affect the affinity for 5-HT1A significantly. To the highest affinity for 5-HT1A and 5-HT7 receptors with Ki values
understand the binding pattern, compound 6 was docked at 5- of 0.84 and 12 nM respectively.
HT1A active site where it showed a different binding pattern as It also possesses significant serotonin reuptake inhibitory
compared to buspirone. Compound 6 bound at different pocket (RUI, IC50 = 100 nM) activity. In compounds with phenylpiper-
Figure 4. Piperazine-based antidepressants reported by Gu et al..

Reviews
azine moiety, it was observed that substitution at 2nd position of receptors affinities. Compounds 10 and 11 inhibited the
phenyl group is important for serotonin reuptake inhibitory serotonin reuptake with IC50 values of 31 and 25 nM respec-
activity as well as an affinity for 5-HT1A and 5-HT7 receptors tively. Similarly, compounds 10 and 11 showed affinities for 5-
along with spacer linkage of two carbons. Taking lead from this, HT1A and 5-HT7 receptors with Ki values of 62 and 12 nM (10)
another series with phenyl substitution at second position of and 28 and 3.3 nM (11), respectively. The SAR studies revealed
phenyl group of phenylpiperazine was synthesized. It was that the presence of fluoro group at substituted phenyl ring
found that mono- or di-methyl substitution at this aromatic leads to an increase in 5-HT reuptake inhibitory activity.
group lead to selective inhibitors of 5-HT1A/5-HT7 with weak Substitution of fluoro group at the fourth position of the central
activity against serotonin reuptake. Replacing of methyl group benzene ring caused an increase in 5-HT reuptake inhibitory
with methoxy or fluoro did not lead to any improvement in the action. Similarly, the chain length three carbon atom was
activity or reduced the activity further. These results indicated appropriate for 5-HT reuptake inhibition and 5-HT1A/5-HT7
that substitution at this ring is not suitable for serotonin receptors affinities. Compounds having benzofuran moieties
reuptake inhibitory activity. Replacement of diphenyl group by possess more potent 5-HT reuptake inhibitory activity as
benzo[d]isothiazole leads to an increase in serotonin reuptake compared to compounds bearing 5-carbonitrile-indole moiety.
inhibitory activity. The most potent compounds, in in vivo The elongation of chain length to four carbons dramatically
forced swimming test, were found to reduces the immobility decreased the 5-HT reuptake inhibitory activity. These potent
time in a dose-dependent manner. inhibitors were further subjected to in vivo mouse forced
The same research group reported another series of novel swimming test (FST) at a dose of 10, 20, and 40 mg/kg/day (PO)
aralkyl piperazine and piperidine derivatives targeting serotonin for determining their antidepressant activities. Both the com-
receptors.[67] The results from in vitro studies against serotonin pounds were found to reduce the immobility time in dose-
receptors revealed that compound 9 (Figure 4) possesses the dependent manners. Additionally, compound 11 showed a safe
highest affinity toward serotonin receptors 5-HT1A and 5-HT7 profile with very low chances of cardiac toxicity (IC50 =
with Ki values of 6.3 and 0.9 nM, respectively. It inhibited the 16.66 μM) in hERG channel binding assay. It also showed a
serotonin reuptake with an IC50 value of 1.3 nM. In FST and TST, multitargeting profile by showing an affinity for a1-adrenocep-
these compounds were found to reduce the immobility time in tor (Ki = 28 nM).
mice in a dose-dependent manner. Potent compounds were Jankowskaa et al. synthesized a series of novel anilide and
further subjected to in vitro microsomal stability and the result benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-
revealed that compounds are metabolically stable. SAR studies yl)alkanoic acids as ligands targeting 5-HT1A/5-HT7 receptors and
revealed that the compound with a chain length of three PDE4B/PDE7 A simultaneously.[69] The molecules were designed
carbons possesses the highest 5-HT reuptake inhibitory activity using a structure-based drug design approach in which a total
coupled with more than 90 % 5-HT1A/5-HT7 inhibition. Addition- of 33 ligands were identified as lead. These studies revealed
ally, the substitution of thiophen-3-yl in place of six-member compound 12 (Figure 5) as most potent antagonist of 5-HT1A
substituent possesses high inhibitory activity for 5-HT1A, 5-HT7, (Ki = 8 nM and Kb = 0.04 nM) and 5-HT7 (Ki = 451 nM and Kb =
and serotonin reuptake. 460 nM) possessing PDE4B and PDE7 A inhibitory activities with
Taking lead from previous studies, same research group IC50 values of 80.4 and 151.3 μM, respectively. Further, from
synthesized and evaluated a series of 21 aralkyl piperazine cellular-based in vitro studies, the compound was found to act
derivatives for their serotonin reuptake inhibitory activities (RUI) as an antagonist of 5-HT1A and 5-HT7 receptors with no
along with 5-HT1A and 5-HT7 receptors affinities.[68] The results activation. From these structure-based and SAR studies, it was
from biological studies revealed that compounds 10 and 11 observed that the chain length of the spacer of four carbons
(Figure 4) possess the most balanced profile for serotonin between 2-methoxyphenylpiperazine and amide moieties is
reuptake inhibitory activities along with 5-HT1A and 5-HT7 most suitable for 5-HT1A and 5-HT7 receptor affinities. Any
Figure 5. SAR studies of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acid derivatives.

Reviews
decrease (three carbons chain) or increase (five carbons chain) activity. Further, the enzyme kinetic studies revealed that these
in the spacer chain led to a decrease in 5-HT1A and 5-HT7 compounds show mixed-type inhibition of MAO A. In docking
receptor affinity. These results also verified the earlier studies studies, compound 13 was found to fit well at the active site of
reported for purine-based 5-HT1AR ligands.[70–71] In membrane MAO A (PDB ID: 2Z5X) lined by amino acid residues Ile180,
permeability assays, compound 12 was found to possess high Asn181, Phe208, Gln215, Leu337, and Phe352. The C=O group
oral absorption and high ability of passive transportation across of 13 was found to form a hydrogen bond with the NH2 group
cell membranes. During in vitro rat liver microsomes (RLMs) of Gln215 amino acid residue. Similarly, the nitrogen atom of
metabolic studies, compound 12 was found to be highly stable. one piperazine fragment showed π-cation interaction with
Encouraged from positive in vitro results, compound 12 was Phe208 amino acid residues while nitrogen atom of other
subjected to in vivo behavioral studies like novel object piperazine fragment showed π-cation interaction with Leu337
recognition and forced swimming test (FST) in Wistar rats at amino acid residues.
doses of 1, 3, and 10 mg/kg (i. p.). From these studies, Monoamine oxidase-A is a key target for designing anti-
compound 12 was found to reduce the immobility time in the depressant ligands.[73,74] Based on this literature survey, Kumar
FST by 34 % at a dose of 10 mg/kg. In open field studies, et al. designed and synthesized two series of piperazine
compound 12 does not improve locomotor activity which derivatives in which one 4-substituted phenylpiperazine and
shows the specific character of its antidepressant activity. Thus, second is of 1-benzhydrylpiperazine derivatives.[75] The synthe-
reduction in immobility times also proves its sedative effect in sized derivatives were evaluated for their MAO inhibitory
animals. activity against both MAO A and MAO B using fluorometric
Kaya et al. designed and synthesized a series of 2-[4- Amplex Red assay. The results of in vitro studies revealed
(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-substituted pipera- compound 15 (Figure 6) as the most potent MAO A inhibitor
zine-1-carbodithioate derivatives as potential monoamine with an IC50 value of 120 nM while compound 16 (Figure 6)
oxidase-A (MAO A) inhibitors.[72] The synthesized derivatives possesses the most potent MAO B inhibitory activity with IC50
were evaluated for their activity against MAO A as well as value of 80 nM. The benzhydrylpiperazine derivative 17 (Fig-
MAO B using fluorometric studies. The synthesized compounds ure 5) was found to possess the highest selectivity for MAO A
were found to possess better MAO A inhibitory activity over with IC50 value of 320 nM with selectivity index of tenfold over
MAO B. The results from in vitro enzymatic assays revealed MAO B. SAR studies revealed that the substitution of nitro
compounds 2-[4-(pyrimidin-2-yl)piperazin-1-yl]-2-oxoethyl 4-(4- group on the fourth position of phenyl ring leads to an increase
nitrophenyl)piperazine-1-carbodithioate (13) and 2-[4-(pyrimi- in selectivity for MAO A. Similarly, the replacement of benzoyl
din-2-yl)piperazin-1-yl]-2-oxoethyl 4-benzhydrylpiperazine-1- group with phenylsulfonoyl group lead to an increase in
carbodithioate (13; Figure 6), as selective inhibitors of MAO A MAO A inhibitory activity significantly. These results were in
with IC50 values of 23.10 and 24.14 μM, respectively. The SAR agreement with the literature which states that the compound
studies revealed that substitution with aromatic moiety at para with polar and electron-donating groups possesses more
position of piperazine is important for MAO A inhibitory affinity towards MAO A while compounds with hydrophobic
Figure 6. SAR studies of piperazine derivatives as MAO inhibitors.

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bulky group possess more affinity towards MAO B. Moreover, ylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine

in reversibility studies, compounds 15 and 17 were found to hydrochloride (19, Figure 7) was identified to possess the
possess reversible inhibitor character against MAO A. To under- highest affinity for 5-HT1A (Ki = < 1 nM) and for 5-HT7 (Ki =
stand their binding pattern, most compounds were subjected 34 nM) receptors. These results were better than that of
to molecular docking studies, from the results it was found that serotonin and buspirone. In tail suspension test, compound 19
the benzhydrylpiperazine moiety of compounds 15 and 17 is was found to decrease the immobility time in mice by 41.6 and
oriented towards FAD cofactor while the sulfonyl group aligned 54.5 % at the dosage of 2.5 and 5 mg/kg respectively. These
itself toward the hydrophobic pocket at the active site of results were better than imipramine which showed reduction in
MAO A. immobility time by 52.4 % at dosage of 5 mg/kg. At these doses,
Kubacka et al. reported the design, synthesis, and biological compound 19 was found unable to locomotor activity in mice
evaluation of series of novel aroxyalkyl derivatives of 2-meth- while at doses of 30 and 60 mg/kg, it reduced the locomotor
oxyphenylpiperazine as antidepressant compounds.[76] From activity significantly by 51.4 and 87.8 % respectively. Its ED50
in vitro studies against serotonin receptors, 1-[3-(2,6-dimeth- value was found to be 17.5 mg/kg. SAR studies revealed that
ylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine ethoxyethyl derivatives of piperazine are as active as other but
hydrochloride (18, Figure 7) was identified with the most less neurotoxic. In the case of substitution of dimethyl group in
balanced profile against 5-HT receptors. It was found to possess reference compound 4-[(2,6-dimethylphenoxy)propyl]-1-(2-
partial agonist activity against 5-HT1AR (Ki = 0.5 nM), antagonist methoxyphenyl)piperazine hydrochloride at phenyl ring at the
property against 5-HT2AR (Ki = 138.5 nM) and high affinity for 5- second and fifth positions favors the affinity for 5-HT1A and for
HT7R (Ki = 34 nM). During in vivo tail suspension studies, com- 5-HT7 receptors with Ki values less than 1 nM along with
pound 18 was found to reduce the immobility time in mice by reduction in neurotoxicity.
52.4 % at dosage of 2.5 mg/kg. Similarly, in the forced Pytka et al. reported two piperazine scaffold bearing
swimming test, compound 18 showed antidepressant activity compounds 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-
by reducing immobility time by 46.4 % at dosage of 10 mg/kg. methoxyphenyl)piperazine hydrochloride (19) and 1-[(2,6
Moreover, compound 18 was also found to possess anxiolytic dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine
activity in four plate tests in mice. It increased the number of hydrochloride (20) as potential antidepressant and memory-
punished crossing accepted by mice by 59.4 % at dosage of enhancing agents.[78] Both the compounds were evaluated for
10 mg/kg. Radioligand binding studies further confirmed the in vivo antidepressant activities using a forced swimming test.
highest binding affinity of compound 18 for 5-HT1A receptor Compounds 19 (HBK-15) and 20 (HBK-14; Figure 7) showed
subtype. It was also concluded that 2-methoxyphenylpiperazine good antidepressant as well as memory-enhancing properties.
derivatives possess α2-adrenoceptor antagonistic property that After 21 days of treatment, 20 reduced the immobility time in
plays a key role in the treatment of depression. mice by 21 % while increased the swimming time by 67 %.
Waszkielewicz et al. reported the synthesis and antidepres- Compound 19 reduced the immobility time by 19 and 29 %
sant activity of N-(2-methoxyphenyl) piperazine derivatives.[77] respectively while increased the swimming duration by 75 and
The synthesized compounds were subjected to various in vitro 111 %, respectively. These results were similar to standard
(5-HT1A, 5-HT6, and 5-HT7 receptors) and in vivo (Tail suspension antidepressant fluoxetine. Compound 19 possessed weak
test, locomotor activity, and motor coordination test) studies to cholinergic activity too. In scopolamine-induced cognitive
determine their biological potential. During in vitro studies, all dysfunction studies, both compounds showed little memory-
the compounds were found to possess a good affinity for 5- enhancing properties also. In another study, compounds 19 and
HT1A and 5-HT7 receptors. In these studies, 1-[(2-chloro-6-meth- 20 displayed high affinity for adrenergic α1 receptors.[79] Both
Figure 7. SAR studies of 2-methoxyphenylpiperazine derivatives as antidepressants.

Reviews
the compounds showed a moderate affinity for SERT and 5-HT2A Can et al. developed a series of novel piperazine incorpo-
receptors while no affinity for adrenergic α2 and β1 receptors. rated thiadiazole derivatives and evaluated for antidepressant
In mechanistic studies, both the compounds showed antago- activity by using tail-suspension (TST) and modified forced
nistic properties toward 5-HT1A and 5-HT7 receptors. swimming (MFST) methods.[82] The target compounds were
Han et al. synthesized two different series of a total of 49 synthesized via reaction of acetylated 2-aminothiadiazole with
1,4-disubstituted piperazine derivatives as triple reuptake appropriately substituted piperazine derivatives in presence of
inhibitors with antidepressant activity.[80] The antidepressant potassium carbonate base. Target compounds were subjected
activity of synthesized compounds was evaluated using neuro- to tail-suspension test (TST) and modified forced swimming test
transmitter transporter uptake assay kit (Molecular Devices, (MFST) for evaluation of their antidepressant activities. These
Sunnyvale, CA, USA) against dopamine (DA), norepinephrine studies revealed that compounds 23 and 24 (Figure 9) possess
(NE), and serotonin neurotransmitters. In these studies, com- potent antidepressant activity similar to fluoxetine and reduce
pounds with benzamide moiety were found to possess better the immobility time in mice significantly. Similar results were
reuptake inhibitory activity for serotonin transporters (SERT), observed in MFST and compounds 23 and 24 were identified as
norepinephrine transporters (NET), and dopamine transporters the most potent antidepressant ligands. In MFST, both the
(DAT) as compare to compounds having simple amide moiety compounds decreased the immobility time and increased
(amide group in between piperazine and nitrogen atom). From swimming activity. These results suggested that the antidepres-
this series, 21 (Figure 8) was found to possess the most potent sant activity of these ligands might be associated with a
triple reuptake inhibitory activity by inhibiting SERT, NET, and serotonergic mechanism. These facts were further proved via
DAT by 91, 91, and 88 %, respectively, at a concentration of no changes observed in vertical or horizontal locomotor
10 μM. activities. From SAR studies, it was observed that substitution of
Ozkay et al. synthesized novel piperazine bearing benzo- bulky and hydrophobic phenyl ring on piperazine possesses
thiazole derivatives as potential antidepressant agents.[81] The potent antidepressant activity. Replacing these with small
synthesized derivatives were evaluated for their antidepressant methyl or thioethyl group leads to a significant loss of
activities using tail suspension test, modified forced swimming antidepressant activity. With negligible toxicity, these com-
test (MFST), and activity cage test. The results of in vivo studies pounds provide new insights into the development of novel
revealed that compounds bearing piperazine moiety reduce the piperazine-based antidepressant compounds.
immobility time in mice in tail suspension as well as modified Tokgoz et al. synthesized a series of novel piperazine
forced swimming test as compared to compounds which do bearing benzazole derivatives as potential antidepressant
not have piperazine moiety. Compound 22 (Figure 8) was found agents.[83] The target compounds were synthesized by reacting
to possess the most potent activity in this series and reduced 2-(benzazol-2-ylthio)acetohydrazide with appropriate 4-pipera-
the immobility time most significantly. SAR studies revealed zine substituted benzaldehydes in ethanol solvent. The anti-
that substitution of benzyl or phenyl at the fourth position of depressant activity of synthesized derivatives was evaluated
piperazine possesses a potent antidepressant profile and good using tail-suspension test (TST) and modified forced swimming
penetration capacity to the CNS. Extension of the chain length test (MFST). The results were encouraging as these compounds
between piperazine and phenyl group leads to decrease in were found more effective as compared to fluoxetine. In MFST
antidepressant activity. compounds 25 and 26 (Figure 10) reduced the immobility time
along with increasing the swimming time most significantly,
similar to fluoxetine. Such results indicate that target com-
pounds were showing antidepressant effects via acting on
serotoninergic system. No alterations in horizontal or vertical
locomotor activities further suggested that antidepressant
action of this compound is specific and the underlying
Figure 8. SAR studies of piperazine derivatives as antidepressant com- Figure 9. SAR of novel piperazine incorporated thiadiazole derivatives as
pounds. antidepressants.

Reviews
antidepressant action of the compound is via action on 5-HT1A

receptors. Further, LQFM104 was found to possess anxiolytic
activity. The use of pCPA also reversed the antidepressant and
anxiolytic activity of LQFM104 to further confirm these results.
These results were in correspondence with the development of
CNS active agents and provide important insights into this field.
Glycogen synthase kinase-3β (GSK-3β) is also reported to
play a key role in major depression.[85] Khan et al. synthesized a
series of novel piperazine bearing pyrimidine-4-one derivatives
as antidepressant agents acting via inhibition of glycogen
synthase kinase-3β.[86] From this series, 3-methyl-6-phenyl-2-
(piperazin-1-yl)-3,4-dihydropyrimidin-4-one (27; Figure 11), pos-
sessed the most potent GSK-3β inhibitory activity with IC50
Figure 10. SAR of piperazine bearing benzazole derivatives as potential value of 74 nM. During in vivo tail suspension studies, this cyclic
antidepressant agents.
secondary amine-pyrimidone conjugate (28) reduced the
immobility time (197 sec) significantly as compared to the saline
group (234 s). Similarly, in the case of FST, compound 28 also
mechanism is via 5-HT1A, 5-HT2A/2C, and 5-HT3 receptors. The reduced the immobility time significantly (p < 0.05) as com-
anti-immobility action of NAN-190, ketanserin, and ondansetron pared to fluoxetine and normal saline groups at dose of 50 mg/
further confirmed that antidepressant action of target com- kg. The SAR studies revealed that substitution of the electron-
pounds is through 5-HT1A, 5-HT2A/2C, and 5-HT3 receptors. SAR donating group at phenyl moiety substituted to piperazine is
studies indicated that the replacement of benzimidazole with important for potent antidepressant activity. The substitution of
benzthiazole does not affect the antidepressant activity. Com- halogen group on phenyl moiety showed marked antidepres-
pounds substituted with methyl and ethyl groups at the fourth sant activity as compares to alkoxy group. In docking studies,
position of piperazine ring showed better antidepressant compound 28 showed a docking score of 5.962 by forming
activity as compared to compounds bearing iso- or cyclopropyl hydrogen bonds with Val135 present at the active site of GSK-
moieties. 3β. The results of docking studies were found in agreement
Da Silva et al. synthesized a novel tert-butyl 4-((1-phenyl-1H- with the in vitro GSK-3β inhibition studies.
pyrazol-4-yl) methyl) piperazine-1-carboxylate (27, LQFM104) Kumar et al. reported the synthesis and biological evalua-
derivatives as potential antidepressant agents acting via the tion of a series of novel 1-[[3-(furan-2-yl)-5-substituted phenyl-
serotoninergic system.[84] In open field studies, the time spent 4,5-dihydro-1,2-oxazol-4-yl]methyl]-4-methyl piperazine
for grooming, fecal bolus, number of total areas crossed, derivatives.[87] The antidepressant activity of synthesized deriva-
rearings, and the immobility time were unaltered while in tives was evaluated using forced swimming test (FST) in albino
elevated plus maze test it increased the percentage open arm mice. The results of these in vivo studies revealed that
entries (%OAE) and percentage time spent in open arms (% compounds 1-[[3-(furan-2-yl)-5-(4-N,N-dimethylaminophenyl)-
TOA) at doses of 50 and 100 mg/kg significantly. In FST, 4,5-dihydro-1,2-oxazol-4-yl]methyl]-4 methyl piperazine (29), 1-
LQFM104 (27, Figure 11) reduced the immobility time by 17 [[3-(furan-2-yl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]methyl]-4
and 21 % at doses of 25 and 50 mg/kg, respectively. This effect methyl piperazine (30), and [3-(furan-2-yl)-5-(4-methoxyphenyl)-
was reversed by use of WAY100635; this suggested that the 4-((4-methylpiperazin-1-yl)methyl)-4,5-dihydroisoxazole] (31)
Figure 11. LQFM104 and SAR of GSK-3β inhibitors of piperazine derivatives.

Reviews
possess the potent antidepressant activity by reducing the studies revealed that phenyl moiety at distal nitrogen atom of
immobility time in mice significantly as compared to control at piperazine ring plays a key role in 5-HT3 antagonist activity.
dose of 10 mg/kg. The SAR studies revealed that compounds With the increase in spacer length between piperazine and
with no substitution or having N,N-dimethyl or methoxy group phenyl group from 0 to 1 carbon leads to a decrease in the
at para position of phenyl ring attached to isoxazoline moiety activity. Further, the compounds were subjected to in vivo
favors the antidepressant activity. Further, compounds 29 and forced swimming test (FST) for determination of antidepressant
30 (Figure 12) were found to possess potent anxiolytic activity activity. The result of FST showed that compounds 32 and 33
in mice without any neurotoxicity. These compounds, 29 and (Figure 13) possesses potent antidepressant activity and re-
30 were subjected to docking studies at the active site of duced the immobility time significantly as compared to
MAO A. Compound 30 was found to show hydrogen bonding ondansetron.
with Gly22, Ser24, and Arg45 amino acid residues present at the Partyka et al. synthesized two series of 8-unsubstituted 7-
active site of MAO A while compound 29 formed the hydrogen phenylpiperazin-4-yl-alkyl and 7-tetrahydroisoquinolinyl-alkyl
bonding with Ala68 and Tyr69. derivatives and evaluated their affinity towards 5-HT1A, 5-HT2A,
Dhar et al. reported the design and synthesis of novel 5-HT6, 5-HT7 and dopamine D2 receptors.[89] During these in vitro
piperazine derivatives of naphthyridine-3-carboxamides and studies, compounds 34 and 35 (Figure 14) were found to
indole-2-carboxamides possessing 5-HT3 receptor antagonist possess the highest affinity toward 5-HT1A receptors with some
properties along with antidepressant activity.[88] The 5-HT3 affinity toward 5-HT7 and dopamine receptors. Compound 34
receptor antagonistic activity of the synthesized derivatives was showed the most promising profile against 5-HT1A, 5-HT2A, 5-
evaluated on isolated guinea pig ileum using 5-HT3 specific HT7, and dopamine D2 receptors with Ki values of 1 � 0.8, 102 �
agonist, 2-methyl-5-hydroxytryptamine. The results from these 11, 479 � 32, and 195 � 11 nM, respectively. Compound 35 also
studies revealed that indole-2-carboxamide piperazine deriva- showed a good affinity for 5-HT1A, 5-HT2A, 5-HT7, and D2
tive 32 and naphthyridine-3-carboxamide piperazine derivative receptors with Ki values of 5 � 0.4, 54 � 6, 131 � 9, and 40 � 5
33 possess the most potent 5-HT3 antagonist activity. SAR nM, respectively. SAR studies revealed that spacer chain length
of four to five carbon atoms in 7-phenylpiperazinylalkyl
derivatives is most favorable for 5-HT1A receptor as well as 5-HT7
receptor affinities. The increase in spacer length from propylene
to butylene greatly enhanced the 5-HT1A and 5-HT7 receptor
affinities. The 3-chlorophenylpiperazine moiety of compound
35 occupied the more conserved pocket present in between
transmembrane helices (TMHs) 3–6. It showed the charge
forced hydrogen bonding with key amino acid residue Asp3.32
present at this active site. It also formed an aromatic cluster
with Phe6.52 of TMH6. On other hand, compound 34 aligned
itself between TMHs 1, 2, and 7 via forming hydrogen bonding
with Asn7.39 amino acid residue.
Same research group also reported two novel imidazopur-
Figure 12. SAR of 1-[[3-(furan-2-yl)-5-substituted phenyl-4,5-dihydro-1,2-oxa- ine-2,4-dione derivatives, namely 8-(4-(4-(2-fluorophenyl)
zol-4-yl]methyl]-4-methyl piperazine derivatives. piperazin-1-yl)butyl)-1,3-dimethyl-1H-imidazo[2,1-f]purine-
Figure 13. SAR of piperazine derivatives of naphthyridine-3-carboxamides and indole-2-carboxamides possessing.

Reviews
Figure 14. SAR of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl and 7-tetrahydroisoquinolinyl-alkyl derivatives.
2,4(3H,8H)-dione (36, AZ-853), and 1,3-dimethyl-8-(4-(4-(3- via binding at 5-HT1A receptors. Compound 36 (AZ-853) showed
(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f] a more predominant antidepressant activity as compared to 37
purine-2,4(3H,8H)-dione (37, AZ-861), as 5-HT1A partial agonist (AZ-861) which might be due to its better penetration ability
and antidepressant agents.[90] Both the compounds 36 and 37 into brain parts.
(AZ-853 and AZ-861; Figure 15) showed full or partial agonistic Pytka et al. reported another novel piperazine bearing
activity against 5-HT1A receptors. Both the compounds inhibited xanthone derivative 38 (HBK-6), 3-chloro-5-[[4-(2-hydroxyethyl)
cAMP formation significantly as compared to serotonin. These piperazin-1-yl]methyl]-9H-xanthen-9-one dihydrochloride as a
also initiated β-arrestin recruitment as similar to serotonin with potential antidepressant agent.[91] The compound was subjected
the same efficacy and potency. In FST studies, compound 36 to in force swim test (FST) for determination of antidepressant
displayed stronger antidepressant activity via reducing immo- activity along with locomotor activity (to determine the
bility time in mice by 50, 58, and 45 % at doses of 0.625, 1.25, specificity of effect) and rotarod test (to determine neuro-
and 2.5 mg/kg, respectively. On other hand, compound 37 toxicity). The results of FST revealed that 38 (HBK-6; Figure 15)
reduced the immobility time in mice by 33 % at dose of reduce the immobility time in mice at dose of 2.5 mg.kg when
1.25 mg/kg. Pretreatment with WAY100635 along with 36 (AZ- given along with fluoxetine (5 mg/kg). Although, when given
853) reversed its antidepression action which proves that it acts alone both fluoxetine (10 mg/kg) and 38 (HBK-6; 5 mg/kg) do
Figure 15. Various piperazine-based antidepressant compounds under development.

Reviews
not affect immobility time significantly. Due to the low affinity (SIPI5358, 5-HT IC50 = 1.59 μM; NE IC50 = 1.50 μM; DA IC50 =
of this compound toward serotonin and adrenergic receptors,[92] 1.30 μM) showed less and equal potency for all the monoamine
further studies were performed to understand the underlying transporters. Moreover, the d-conformations of both derivatives
mechanism behind the antidepressant effect. Compound 38 were found to possess more potent triple inhibitory activity as
(HBK-6) showed potential antidepressant effect when given in compared to their l-conformations. Both compounds SIPI5357
combination with fluoxetine (SSRI) but showed no effect when and SIPI5358 were found to reduce the immobility time
given in combination with reboxetine (SNRI), and bupropion significantly in a dose-dependent manner in FST and TST.
(dopamine and noradrenaline reuptake inhibitor) which suggest Wrobel et al. synthesized a series of novel 4-butyl-arylpiper-
the possible mechanism involved serotonergic pathway. It was azine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives and eval-
further confirmed via pre-treatment studies using pCPA, uated for their biological potential in vitro for 5-HT1A and D2
inhibitor of serotonin biosynthesis. receptors affinity and serotonin reuptake inhibitory activity.[96]
Same research group reported two xanthone derivatives 6- Most of the synthesized compounds displayed a good affinity
methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9- for 5-HT1A receptors. From this series, compound 43 (Figure 16)
one (HBK-7, 39),[93] and 6-methoxy-2-[4-(2-methoxyphenyl) was identified to possess the highest affinity towards 5-HT1A
piperazin-1-yl]-9H-xanthen-9-one (HBK-11 40;[94] Figure 15) with receptors with a Ki value of 0.4 � 0.03 nM. Similarly, compound
potential antidepressant activity in two different studies. Both 44 was identified to possess promising triple inhibitory activity
the compounds showed a good affinity for 5-HT1A receptors as for 5-HT1A, D2, and serotonin transporter inhibition with Ki
with Ki values of 30 nM (Kb value 23 nM) and 429 nM, values of 1.3, 182, and 64 nM, respectively. It was observed that
respectively. Compound 40 (HBK-11) showed a moderate the affinity of synthesized derivatives toward these targets is
affinity for 5-HT2A, 5-HT6, and 5-HT7 receptors with Ki values of greatly affected by the substitution pattern at phenylpiperazine
561, 13 600, and 1100 nM, respectively. In FST studies, com- moiety. SAR studies revealed that substitution with halogen
pounds 39 (HBK-7) and 40 (HBK-11) reduced the immobility (specially 2-F) at the ortho position of phenylpiperazine
time by 24 and 32 % (50 % at 20 mg/kg), respectively, at dose of increases the affinity towards 5-HT1A receptor. On moving,
10 mg/kg in mice. Compound 39 (HBK-7) was found to increase substitution from the ortho to para position decreased the
the swimming time by 123 % at same dose which describes the affinity towards 5-HT1A receptors but interestingly enhanced
specific antidepressant activity of this compound. The antide- SERT inhibitory activity.
pressant action of both the compounds was reversed by p- Modica et al. reported novel long-chain 4-substituted piper-
chlorophenylalanine pre-treatment which describes their target azines linked to a thienopyrimidine or quinazolines as 5-HT1A
specificity. and 5-HT7 dual targeting ligands.[97] The synthesized com-
Weng et al. reported the synthesis of erythro/threo race- pounds were evaluated for their binding affinity against human
mates and their four optical isomers of 2-(4-benzylpiperazin-1- cloned 5-HT1A and 5-HT7 serotonin receptors. The results from
yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol and sub- these studies revealed that compounds 45 and 46 (Figure 17)
jected to various biological studies to determine their anti- possessed the highest affinity for 5-HT1A receptors with Ki values
depressant potential.[95] The compounds were evaluated using of 1.04 � 0.13 and 1.03 � 0.07 nM, respectively, as well as for 5-
in vivo TST and FST along with their triple reuptake inhibitory HT7 receptors with Ki values of 6.88 � 0.66 and 2.99 � 0.60 nM,
(5-HT, NE, and DA) activities. The results of these pharmaco- respectively. SAR studies revealed that binding affinity is greatly
logical studies revealed that erythro compound 41 (SIPI5357, affected by arylpiperazine moiety rather than alkyl chain length
Figure 15) possesses potent triple reuptake inhibitory with IC50 or terminal amide moiety. Ortho-ethoxy groups at phenyl-
values of 0.87, 1.40, and 0.96 μM for 5-HT, NE, and DA, piperazine fragment are most suitable for 5-HT1A and 5-HT7
respectively. It was found to possess more selectivity for 5-HT targeting. Opposite to as expected, the substitution of chloro
and DA as compared to NE. On other hand threo derivative 42 group at the third and fourth positions of phenylpiperazine
Figure 16. SAR studies of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives.

Reviews
Kucwaj-Brysz et al. explored receptor–ligand interactions for

lead 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)
piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione as 5-HT7
receptor agents with antidepressant activity.[99] In initial com-
puter-aided studies, the interactions required for potent ligands
including a salt-bridge with Asp3.32, π–π or π–cation inter-
actions of 2-ethoxyphenylpiperazine moiety with Phe6.51 and
Phe6.52 of side chain, π–π interactions with Phe3.28 and a
hydrogen bonding of hydantoin moiety with Cys146 of ECL2 of
5-HT7 receptor were observed. Based on these findings, ligands
were designed, synthesized and evaluated for their pharmaco-
logical profile. Most of the synthesized compounds were found
to possess high affinity (Ki < 0 nM) for 5-HT7 receptors in radio-
ligand binding assay. Compound 49 (Figure 19) displayed the
Figure 17. SAR studies of long-chain 4-substituted piperazines linked to a highest affinity for 5-HT7 receptors with Ki value of 6 nM. It also
thienopyrimidine or quinazolines. displayed a moderate affinity for 5-HT1A receptors with Ki value
of 100 nM but no or very low affinity for adrenergic receptors.
Further, in vivo antidepressant and anxiolytic activities were
reduced the selectivity towards 5-HT7 receptors. In preliminary determined using FST and four-plate methods (FPT) respec-
studies, both the compounds were found to act as an tively. In this compound 50 (Figure 19) displayed the most
antagonist of these receptors. potent antidepressant activity and reduced immobility time in
Kedzierska et al. synthesized a series of novel arylpiperazine mice by 80 % at dose of 20 mg/kg. The results observed were
derivatives possessing isonicotinic and picolinic moieties as a similar to standard antidepressant drug imipramine. The SAR
serotonergic system modulator with antidepressant activity.[98] studies indicated that replacement of p-fluoro group with
N-(3-(4-(Piperonyl)piperazin-1-yl)propyl) isonicotinamide (47), bigger halogen or methoxy and methyl groups does not
and N-(2(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide produce a significant effect on the activity of these compounds.
(48), were found to possess potent affinity for 5-HT1A receptors Panczyk et al. reported the design and synthesis of a novel
with Ki values of 0.0113 and 0.046 nM, respectively. Moreover, series of N-(phenoxyalkyl)-, N-[2-[2-(phenoxy)ethoxy]ethyl]-, or
compound 47 (Figure 18) showed a significant affinity for 5- N-(phenoxyacetyl)piperazine derivatives having potent antide-
HT2C receptors with Ki value of 2.19 nM. In TST, both the pressant-like, anxiolytic and anticonvulsant activity.[100] The
compounds showed potent antidepressant-like action. Com- results of FST revealed that 1-[4-(2,5-dimethylphenoxy)butyl]-4-
pound 48 (Figure 18) acted as a presynaptic 5-HT1A receptor phenethylpiperazine dihydrochloride (51) has antidepressant
antagonist and a postsynaptic 5-HT1A receptor partial agonist. like activity which is lower than fluoxetine. In radioligand
Similarly, compound 47 was found to act as a presynaptic 5- binding assays, compound 51 (Figure 20) showed a low affinity
HT1A receptor agonist which describes that its antidepressant for serotonin receptors (Ki value of 812 nM for 5-HT2A, 336 nM
action is not only limited via action at 5-HT1A receptors but also for 5-HT6, and 659 nM for 5-HT7) with no binding for 5-HT1A
affects 5-HT2C receptors. In FST, pretreatment with pCPA receptors. It also showed a weak affinity for dopamine D2 and
reversed the antidepressant action of these target compounds adrenergic receptors which describe that the antidepressant-
which further confirm their action via serotonergic system.
Further, on pretreatment with WAY 100635, the antidepressant
action was completely blocked which confirmed the specificity
of compounds 47 and 48 for 5-HT1A receptors. In locomotor
activities, both the compounds were found ineffective which
reduce the risk of false-positive results in antidepressant
activity. In an elevated plus-maze (EPM) test, both the target
compounds were found to possess anxiolytic activity.
Figure 18. Arylpiperazine derivatives possessing isonicotinic and picolinic Figure 19. Structural insights on phenylpiperazinyl compounds as antide-
moieties. pressants.

Reviews
Figure 20. SAR of N-(phenoxyalkyl)-, N-[2-[2-(phenoxy)ethoxy]ethyl]piperazine derivatives as antidepressants and PPMP.
like activity of these compounds might be due to some other behind its antidepressant activity. Further, in vitro (by using
mechanism. From SAR studies, it was observed that molecules neutral red in basal line 3T3) and in vivo (according to the
having substitutions at the second and sixth positions of the recommendations of the Organization for Economic Coopera-
aromatic phenyl group possesses a better affinity for serotonin tion and Development) toxicity studies were performed, and
receptors. The increase in the carbon spacer chain from 2 to 4 the LD50 was found to be 800 mg/kg suggesting its low acute
enhanced the activity. In docking studies, the main interactions toxicity.
of target compounds with serotonin receptors were charge- Ostrowska et al. synthesized novel arylpiperazinyl deriva-
reinforced hydrogen bond by protonated nitrogen atom of tives of 8-acetyl-7-hydroxy-4-methylcoumarin and evaluated
phenylpiperazine and carboxyl group of Asp3.32 and cation-π their antidepressant activity using in vivo tail suspension test
interaction with Phe6.52 amino acid residues. (TST).[102] In initial radioligand binding studies against serotonin
Gladino et al. reported 4-(1-phenyl-1H-pyrazol-4-ylmethyl)- receptors, compounds 53 and 54 (Figure 21) were found to
piperazine-1-carboxylic acid ethyl ester (PPMP, 52), having possess the highest affinity for 5-HT1A receptors with Ki values
antidepressant activity via monoamine systems.[101] The results of 0.50 � 0.05 and 0.60 � 0.05 nM, respectively. Compounds 53
from TST and FST studies revealed that 52 (Figure 20) possesses and 54 also showed a good affinity for 5-HT2A receptors with Ki
potential antidepressant activity by serotonergic and catechola- values of 7.0 � 0.5 and 8.0 � 0.7 nM, respectively. [35S]GTPγS
minergic systems. It significantly reduced the immobility time, binding assay revealed the antagonistic character of both
similar to fluoxetine. In mechanistic studies, it was observed compounds against 5-HT1A receptors. Additionally, compound
that it does not inhibit MAO enzymes. Pretreatment studies 53 was found to possess potent antagonist properties against
with α-methyl para-tyrosine AMPT (nonselective blocker of 8-OH-DPAT with pEC50 of 6.9 � 0.15 as compared to 54 (pEC50 =
catecholamine synthesis) and p-chlorophenylalanine pCPA (5- 6.2 � 0.10; p < 0.01). Compound 54 was found less effective
HT synthesis inhibitor) separately completely blocked the during in vivo studies as compared to 53. SAR studies revealed
antidepressant activity of 52 which further confirmed the that compounds bearing electron-donating group or electron-
involvement of serotonergic and catecholaminergic systems withdrawing group at the ortho position of phenylpiperazine
Figure 21. SAR studies of arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin.

Reviews
ring possess high affinity towards 5-HT1A receptors. Compound antidepressant activity.[105] At doses of 100 and 300 mg/kg, 57
53 was further subjected to docking studies and it was (Figure 22) protected more than half animals from seizures in
observed that the coumarin part of compound forms multiple the MES test at 0.5 h and 4 h intervals. At a dose of 100 mg/kg,
hydrogen bonds at the active site of 5-HT1A receptor. The it showed protection at three-time intervals with ED50 value of
piperazinyl part was located between helices 2, 3, and 7 and 13.3 mg/kg. In FST, compound 57 reduced the immobility time
formed a strong salt bridge with Asp116 (5-HT1A) or Asp155 (5- significantly similar to fluoxetine (50 mg/kg). At higher dose
HT2A). (300 mg/kg), no reduction in immobility time was observed.
Wen et al. designed and synthesized three series of Although in TST, the same reduction in immobility time was
piperazine bearing arylamidine derivatives to improve antide- observed at higher dose of 300 mg/kg as compared to FST.
pressant activity earlier reported 5-HT receptors ligands.[103] Ostrowska et al. synthesized novel piperazine bearing 6-
Initially, synthesized compounds were screened for in vitro acetyl-5-hydroxy-4,7dimethylcoumarin derivatives having high
serotonin (5-HT) and norepinephrine (NE) reuptake inhibitory affinity for 5-HT1A, 5-HT2A, and D2 receptors.[106] The results of
activity. The results from these studies revealed that compound in vitro studies revealed that compounds 58 and 59 (Figure 23)
55, (II-5, Figure 22) possesses the most potent 5-HT and NE possess a high affinity towards 5-HT1A receptors with Ki value of
reuptake inhibitory activity with IC50 values of 620 nM and 1 nM. Both the compounds also showed a good affinity for 5-
10 nM respectively. Further, during in vivo tail suspension test in HT2A receptors with Ki values of 17.5 and 8 nM, respectively. The
rats, compound II-5 displayed significant antidepressant activity compounds 58 and 59 were found to possess less affinity for D2
at dose of 30 mg/kg (p.o.) which was comparable to duloxetine. receptors which describe their selectivity for serotonin receptors
Mishra et al. synthesized a novel series of 1-phenyl-3/4-[4- over dopamine receptors. Further, both the potent compounds
(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives as were subjected to in vivo FST and TST studies and were found
a potential anticonvulsant and antidepressant agents.[104] The ineffective in mice which indicated that these compounds do
results of this study revealed that 1-[4-[4-(4-chloro-phenyl)- not possess any antidepressant activity. These negative results
piperazin-1-yl]-phenyl]-3-phenyl-urea (56) possesses the most discouraged their further development as a search of treatment
potent anticonvulsant and antidepressant activity in the series. for depression.
In the subcutaneous pentylenetetrazole (scPTZ) seizure test, Gupta et al. synthesized a series of novel 17 aryl piperazine
compound 56 (Figure 22) showed significant protection via derivatives to target andropause-associated prostatic disorders
raising the seizures threshold at lower doses which were found and depression.[107] The most potent antiproliferative com-
better than standard drug AED ethosuximide. These compounds were evaluated for in vivo antidepressant activity in
pounds did not show any motor impairment which indicated which compounds 60 and 61 (Figure 24) showed a significant
the safety profile of these target compounds also. Similarly, in beneficial profile. In FST studies at a dose of 20 mg/kg,
FST, compound 56 reduced the immobility times better than compounds 60 and 61 reduced the immobility time signifi-
fluoxetine. Moreover, SAR studies indicated that the presence of cantly by 69.40 and 69.74 % respectively in rats. These results
electronegative atom at phenyl substituted to piperazine is were found better than imipramine (60 mg/kg) and comparable
more favorable for anticonvulsant activity. to fluoxetine (20 mg/kg). Thus, these results represent com-
Kumari et al. synthesized a novel aryl piperazine derivative pound 60 (1,2-bis(4-(pyridin-2-yl)piperazin-1-yl)propane) as a
1-[4-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)- phenyl]-3- potential lead for developing novel ligands for the treatment of
phenyl-urea (BPPU, 57) and evaluated for its anticonvulsant and
Figure 22. SAR studies of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives.

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Figure 23. SAR of piperazine bearing 6-acetyl-5-hydroxy-4,7dimethylcoumarin derivatives.
Figure 24. SAR of arylpiperazines bearing picolinamide.
androgen-sensitive prostatic disorders and associated depres- Magli et al. synthesized a series of arylpiperazine bearing N’-
sion in aged men. cyanoisonicotinamidine and N’-cyanopicolinamidine derivatives
Fiorino et al. developed a series of novel arylpiperazine having various CNS activities.[109] During binding affinities
bearing picolinamide derivatives as potential antidepressant studies against serotonin receptors, compounds 65 and 66
agents.[108] Initially, the synthesized compounds were screened (Figure 25) showed a mixed profile against 5-HT1A and 5-HT2C
for their binding affinities toward serotonin receptors in which receptors. Compound 65 showed a potent affinity with Ki values
compounds 62–64 (Figure 24) emerged as most potential of 21.3 and 11.5 nM against 5-HT1A and 5-HT2C receptors
candidates. Compounds 62–64 showed selective affinity toward respectively. Similarly, compound 66 showed an affinity with Ki
5-HT1A receptors with Ki values of 0.344 � 0.025, 0.183 � 0.003, values of 23.2 and 6.48 nM against 5-HT1A and 5-HT2C receptors
and 0.046 � 0.01 nM, respectively over 5-HT2A and 5-HT2C respectively. In this series, compound 67 showed highest
receptors. SAR studies revealed that binding affinity to affinity for 5-HT2C receptors with Ki value of 21.4 nM. The
serotonin receptors is significantly influenced by substituent on interesting profile of these compounds encouraged the in vivo
piperazine moiety. Compounds bearing pyrimidinyl moiety studies in which antidepressant activity was determined using
coupled via chain spacer of two methylene groups possess the the FST method. In this study, compounds 65–68 at doses of 15
highest affinity and selectivity for the 5-HT1A receptors. Further, and 30 mg/kg significantly reduced the immobility time in mice
the results of FST studies revealed that compounds 62–64 in a dose-dependent manner as compared to the control group.
possess potent antidepressant activity with a reduction in These results were found comparable with the antidepressant
immobility time in mice to various extent. In elevated plus- activity of fluoxetine (15 mg/kg). As these compounds do not
maze (EPM) studies, these three compounds showed good interfere with spontaneous activity, this antidepressant activity
anxiolytic activity too. But to prove their mechanism and is found to be specific. Along with these, compounds 65 and 67
functional character, further in vivo studies are required. also showed good anxiolytic properties. Docking studies
revealed that 65 formed a hydrogen bond with Leu(7.34) and

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Figure 25. Arylpiperazine bearing N’-cyanoisonicotinamidine and N’-cyanopicolinamidine derivatives with various CNS activities.
π-π stacking via pyrid-4-yl group with Trp(3.28) amino acid of amino acid residues of the transmembrane helix (TMH) 6,
residues of 5-HT2C receptor. Similarly, compound 66 formed a specially Phe6.52 were observed. Further, these compounds
hydrogen bond with the side chain of Ser(2.60) and 67 were subjected to FST studies and found that compound 69
possesses π-π stacking interactions with Phe(6.52) and the Trp (Figure 26) reduced the immobility time in mice by 27 % at a
(6.48) amino acid residues. These results present these com- dose of 0.625 mg/kg. Similarly, compound 70 reduced the
pounds as key molecules for further development as an immobility time by 30 % at different doses of 0.625, 1.25, and
antidepressant agent. 2.5 mg/kg.
Czopek et al. synthesized a series of novel piperazine Ali et al. reported the synthesis and computer-aided SAR
bearing 5-arylidenehydantoin derivatives as multitargeting studies of piperazine substituted phenoxyalkyl-1,3,5-triazine
agents with anticancer and antidepressant activities.[110] The derivative as potential serotonin ligands.[111] Using drug design-
in vitro studies against serotonin receptors revealed that 5-(3,4- ing tools considering 71, 4-(4-methylpiperazin-1-yl)-6-
dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1- (phenoxymethyl)-1,3,5-triazin-2-amine, as a lead compound for
yl)butyl)-imidazolidine-2,4-dione (69) and 5-(3-cyclopentyloxy-4- 5-HT6 receptors, three main modifications were introduced.
methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl) These include the introduction of various small substituent
butyl)-imidazolidine-2,4-dione (70) possess the highest affinity groups at the benzene ring, substituted ether linker, and
for serotonin receptors with Ki values of 0.2 � 0.1 and 1.0 � replacement of oxygen in ether linkage with other chalcogens
0.2 nM for 5-HT1A receptors, respectively, while 0.8 � 0.2 and (S, Se). The designed derivatives were synthesized and
1.0 � 0.2 nM for 5-HT7 receptors, respectively. SAR studies evaluated for their 5-HT6 receptor affinity using radioligand
revealed that compounds with four methylene linkers have a binding assay in which most of the compounds showed high to
higher affinity for 5-HT receptors as compared to three meth- moderate affinity. From this series compounds 72 and 73
ylene linkers. Compounds with ortho substitutions were found (Figure 27) were found to possess the highest affinity for 5-HT6
to have better activity as compared to meta and para receptors with Ki values of 11 and 19 nM respectively. These
substituents. These findings were further confirmed via docking compounds also showed a mild affinity for D2 and 5-HT1A
studies describing their binding patterns at receptor sites in receptors. SAR studies revealed that ortho-substituted ether-
which charge-enforced hydrogen bonding between protonated linked 1,3,5-triazines possess more affinity towards 5-HT6R as
nitrogen atom of the ligand and carboxyl group of Asp3.32 and compared to meta- and para-substituted compounds. The
CH-π stacking of an arylpiperazine fragment and aromatic rings replacement of oxygen of ether linkage with selenium and
Figure 26. SAR of piperazine bearing 5-arylidenehydantoin derivatives as multitargeting agents with anticancer and antidepressant activities.

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Figure 27. SAR of triazine clubbed piperazine derivatives.
sulfur lead increase in affinity as well as antagonistic activity compounds were subjected to forced swim test (FST) in mice
towards 5-HT6R. Moreover, docking studies revealed that three and observed that compound 76 reduce the immobility time in
types of interaction i. e. formation of the salt bridge with D3.32, mice by 37 % at the dose of 0.3 mg/kg. SAR studies revealed
CH-π or π-π stacking with F6.52, and formation of a hydrogen that substitution of Cl, F, CH3, CH3O at meta position of phenyl
bond between the carbonyl group of V3.33 and/or A5.42 and is most favorable for high affinity for 5-HT6 receptors as
NH2 group of 1,3,5-triazine ring are key points behind these compared to ortho and para substitutions.
in vitro results. Further, the potent compounds were evaluated Kim et al. synthesized a series of piperazine bearing
for their antidepressant activity by using in vivo force swim test phthalazinone derivatives targeting 5-HT2A, 5-HT2C, and SERT
(FST) and found that compound 72 at the dose of 0.3–3 mg/kg receptors as triple acting small molecules.[113] The in vitro results
reduced the immobility time by 20 %. But compound 73 was revealed compounds 77 and 78 (Figure 28) as potent ligands
found to be inactive in FST. for serotonin receptors and transporter. Compound 77 showed
Lazewska et al. synthesized a series of 4-benzyl-1,3,5-triazine high affinity toward 5-HT2A and 5-HT2C receptors with IC50 values
derivatives with potential modification at lead compound 74, of 104 and 30 nM, respectively. It also inhibit SERT with an IC50
(4-benzyl-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine, to tar- value of 488 nM. Similarly, Compound 78 showed a high affinity
get 5-HT6 receptors.[112] Using pharmacophore- and structure- toward 5-HT2A, 5-HT2C receptors, and SERT with IC50 values of
based approaches with docking various modifications in the 123, 92, and 115 nM respectively. SAR studies revealed that
lead were introduced and ligands were synthesized. The most phthalazinone derivatives having dimethyl substitution at
potent ligands showed a high affinity for 5-HT6 receptors with Ki phenyl ring possess better affinity and activity for serotonin
value between 20 to 30 nM. In radioligand binding assay, it was receptors and SERT. During in vivo antidepressant studies using
observed that compounds 75 and 76 (Figure 27) possess the FST method, both the compounds 77 and 78 showed good
highest affinity for 5-HT6 receptors with Ki value of 20 � 3 nM antidepressant activity and reduced the immobility time in mice
and 22 � 2 nM respectively. To study the molecular mechanism, significantly by 60 and 40 % respectively at different doses.
docking studies were performed at homology model of 5-HT6R. Besides, compound 77 showed a synergetic effect in antide-
In these studies, two main interactions were observed in which pressant studies when given along with fluoxetine and caused
one is the formation hydrogen bond between amino group of drastic reduction in immobility time in mice which was not
1,3,5-triazine and carbonyl oxygen of Ala5.42 and Val3.33 and observable in the case of fluoxetine alone treatment.
the second is CH-π interaction with Phe6.52. The most potent

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3. Piperazine Derivatives in Clinical Trials for

Depression
Some of the piperazine derivatives which are under clinical

trials against depressive disorders are listed in Table 2
(Figures 29 and 30).
Brexpiprazole, a novel serotonin and dopamine
modulator,[114] has completed various phase-III and phase-IV
studies against bipolar depression (NCT03427892,
NCT03149991).[115] NSI-189 completed the phase-I study in
which its pharmacokinetic and pharmacodynamic profile was
evaluated in depression patients (NCT01520649). It also com-
pleted a phase-IB dose-escalation study in which it showed
persistent improvement in depressed patients.[116] In another
double-blind phase-II study, it showed significant improvement
in patients with major depression measured via symptoms of
Figure 28. SAR of piperazine bearing phthalazinone derivatives. depression questionnaire (SDQ) and cognitive and physical
functioning scale (CPFQ).[117]
Lurasidone, a 5-HT1A and 5-HT7 receptor ligand,[118] has
completed phase-III 6- and 24-week studies to determine safety
and efficiency in patients with bipolar depression
(NCT00868699, NCT01284517).[119] Similarly, cariprazine drug, a
D3R ligand,[120] has completed a phase-II study for evaluation of
safety and efficiency in patients with bipolar depression
(NCT00852202). It has also completed a placebo-controlled,
Figure 29. Different piperazine derivatives in clinical studies against different kind of depressive disorders.

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Table 2. Piperazine-based drugs under clinical trials for treatment of depression.

Sr. Name of Study title Year of Clinical trial Reference no.
No compound completion phase and
or status
last entry
1 Brexpiprazole Brexpiprazole for Bipolar Depression 2018 Phase-IV, NCT03427892

A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD) 2017 completed NCT03149991
2 NSI-189 Multiple-Dose Pharmacokinetics (PK), and Pharmacodynamic (PD) Effect of 2014 Phase-I, NCT01520649
Phosphate NSI-189 Phosphate in Depression Patient Subjects completed
3 Lurasidone Lurasidone – A 6-week and 24-week Study of Patients with Bipolar I Depression 2014 Phase-III, NCT00868699
(Monotherapy) 2016 completed NCT01284517
2021 Phase-III, NCT04383691
yet to start
4 Cariprazine Safety and Efficacy of RGH-188 (Cariprazine) in Bipolar Depression 2018 Phase-II, NCT00852202
(RGH-188) completed
5 Quetiapine Brain Imaging of Quetiapine Response in Anxious Depression 2016 Phase-IV, NCT00982345
(Seroquel XR) completed
Pediatric Bipolar Depression 2014 Phase-III, NCT00811473
completed
Neurophysiologic Changes in Patients with Bipolar Depression 2013 Phase-IV, NCT01213121
unknown
6 Vortioxetine Vortioxetine add-on Treatment Improves the Symptoms in Patients with Bipolar 2018 Phase-II, NCT03598868
Depression recruiting
7 Aripiprazole Aripiprazole Augmentation Therapy in Treatment-resistant Depression 2016 Phase-III, NCT00276978
terminated
8 Trazodone A Clinical Study of Trazodone Hydrochloride Prolonged-Release Tablets for Treatment 2014 Phase-II and NCT01524497
of Depression III,
completed
9 Olanzapine Olanzapine Augmentation Therapy in Treatment-resistant Depression: a Double-blind 2016 Phase-III, NCT00273624
Placebo-controlled Trial terminated
10 Mirtazapine Efficacy Study of Mirtazapine to Treat Interferon-related Depression During Antiviral 2020 Phase-IV, NCT01465919
Therapy for Hepatitis C terminated
Efficacy and Safety Analyses of Mirtazapine in NSCLC Patients with Depression 2016 Phase-II, NCT02650544
unknown
11 Bifeprunox Study Evaluating Bifeprunox in Bipolar Depression 2007 Phase-III, NCT00245973
completed
12 Lumateperone Clinical Trial Evaluating Lumateperone Monotherapy in the Treatment of Bipolar 2021 Phase-III, NCT04285515
Depression or Major Depressive Disorder recruiting
Lumateperone Monotherapy for the Treatment of Bipolar Depression 2020 Phase-III, NCT03249376
Conducted Globally completed
13 Ziprasidone An Investigation of Sleep Architecture in Ziprasidone-Treated 2015 Phase-IV, NCT00835107
Bipolar Depression completed
14 Vilazodone Vilazodone for Treatment of Geriatric Depression 2018 Phase-IV, NCT01608295
completed
15 Vardenafil Depression Related Improvement with Vardenafil for Erectile Response (DRIVER) 2014 Phase-III, NCT00661219
completed
16 Orvepitant A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 2017 Phase-II, NCT00880048
Safety of Orvepitant in Subjects with Major Depressive Disorder (Orvepitant MDD) terminated
17 Sildenafil The Phosphodiesterase 5 Inhibitor Sildenafil as an Adjunct to Antidepressants in Major 2020 No applica- NCT04344678
Depressive Disorder Patients tion,
recruiting
18 Zopiclone A Study of Oral Seltorexant as an add-on Medication to an Antidepressant on On-road 2020 Phase-I, NCT04451187
Driving Performance in Participants with Major Depressive Disorder Recruiting
double-blind, phase-III clinical trial for the treatment of mania in (NCT03598868). A phase-III study of aripiprazole was terminated
bipolar disorder.[120] In another phase-III study of cariprazine in due to the risk of late neuroleptic malignant syndrome in
bipolar depression, it was found to be effective, generally well treated patients (NCT00276978)[124] and no new safety signals
tolerated, and relatively safe at both 1.5 and 3.0 mg/day doses were observed.[125] Trazodone, a serotonin modulator,[126] com-
and reduced depressive symptoms in adults.[121] Quetiapine, a pleted the phase-II and III trial in which the efficiency of its
dibenzothiazepine atypical antipsychotic drug,[122] is under prolonged-release tablets was determined in depressive pa-
multiples trails for treatment-resistant and bipolar depression tients (NCT01524497).[127–128] A phase-III study of another drug
(NCT00982345, NCT00253266, NCT01200901, NCT00811473). It olanzapine was also terminated (NCT00273624) as augmenta-
has completed phase-IV trail for brain imaging studies along tion therapy in treatment-resistance depression. Similarly, due
with venlafaxine. Vortioxetine, a multitargeting antidepressant to toxicity issues and adverse effects a phase-IV study
with 5-HT3, 5-HT7, and 5-HT1D receptor antagonist and 5-HT1B (NCT01465919) of miratazapine in NSCLS patients with depres-
receptor partial agonist properties,[123] is under phase-II studies sion was also terminated.
to determine its effect as add on therapy in bipolar disorder

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Figure 30. Different piperazine-based drugs under clinical studies against depression.
Bifeprunox, an atypical antipsychotic drug designed for also provided detailed SAR studies for these derivatives which
schizophrenia,[129] has completed a phase-II study in which provide some consistent information regarding structural
efficiency and effect in bipolar depression were determined feature correlated with the activity throughout diverse preclin-
(NCT00245973). Lumateperone in phase-III clinical studies ical molecules. First one being, flexibility in the molecules
showed marked improvement with CDSS scores in bipolar whereby a linker of generally 3–4 carbon chain connects two
depression (NCT03249376).[130] Ziprasidone is another piperazine aromatic flanks, one of which is coupled with piperazine moiety.
derivative that targets dopamine and serotonin receptors and is Secondly being halogen substitution on the one of the aromatic
used for the treatment of depression.[131] It has completed a flank while hydrogen bond acceptor feature in the other
phase-IV study in bipolar depression and its effect on the sleep aromatic flank. This information can be carried forward to as a
cycle was determined (NCT00835107).[132] Vilazodone has also starting point to develop much needed piperazine-based
completed a phase-IV study in adult patients with depression antidepressants. Various piperazine-based therapeutic agents
(NCT01608295). Sildenafil and vardenafil, two drugs used to which are in early or late phase human testing for depression
treat erectile dysfunction, are also under clinical studies to are also highlighted in this review. Authors believe that the lead
determine their effect on performance in depressed patients or hit compounds discussed in this review will help the
(NCT04344678). Zopiclone, a GABA receptor modulator, is also researchers to design and develop novel piperazine-based
under phase-I study as add on therapy with other antidepres- antidepressant compounds. Overall, this compilation will also
sants in MDD patients (NCT04451187). help in the identification of potent scaffolds that can be
developed as effective drugs for the treatment of depression
with no or minimal side effects.
4. Conclusions and Insights
The World Health Organization (WHO) declared depression to Acknowledgements

be one of the largest contributors to global disability with a
huge economic and social burden on society. Modern lifestyle The authors are thankful to Chairman and Director of ISF College
and habits have increased the incidences of MDD in the young of Pharmacy, Moga, Punjab for supporting this work.
population to great extent and also increased the number of
suicide cases to a large extent. There are number of
antidepressant drugs in the market available for treatment. But Conflict of Interest
treatment-resistant depression, relapse of depression along
with the side effects associated with antidepressants in a large The authors declare no conflict of interest.
count of patients have increased the problems for the clinicians.
Thus, the development of novel antidepressants is the need of Keywords: depression · FST/TST · piperazine derivatives · SAR
time in which piperazine scaffold has played a key role. Due to studies · serotoninergic system
its favorable chemical reactivity and CNS pharmacokinetic
profile, it has emerged as a key pharmacophore in the develop-
ment of antidepressant drugs. This review provided the critical
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204–218. Version of record online: ■■■, ■■■■

REVIEWS
A critical analysis of the significance R. R. Kumar, B. Sahu, S. Pathania,
of the piperazine moiety in the de- Dr. P. K. Singh, Dr. M. J. Akhtar, Dr. B.
velopment of antidepressants. Kumar*
Various piperazine-based therapeutic
1 – 25
agents in early- or late-phase human
testing for depression are discussed. Piperazine, a Key Substructure for
Current developments in designing Antidepressants: Its Role in Devel-
and synthesizing piperazine-based opments and Structure-Activity Re-
antidepressants along with SAR lationships
studies provide crucial clues about
the structural features required to
enhance the efficacy and potency of
the piperazine-based antidepres-
sants.

Kumar 2021

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Piperazine, a Key Substructure for Antidepressants: Its Role

1. Introduction sants selectively inhibit the reuptake of serotonin through its

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Table 1. Various piperazine-based drugs on the market.

serotonin reuptake inhibitor (SERT), norepinephrine reuptake

Buspirone 5-HT1A agonist 1986 [56]

serotonin reuptake inhibitor (SERT), norepinephrine reuptake

Nefazodone 5-HT1AR agonist and 5-HT2R antagonist 1994 [58]

Tandospirone agonist of the 5-HT1A receptor 1990 s [59]

Trazodone 5-HT1AR agonist and 5-HT2R antagonist 1981 [60]

Vilazodone agonist of the 5-HT1A receptor 2011 [61]

serotonin reuptake inhibitor (SERT), 5-HT1AR partial agonist,

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D2 receptor as compared to Fananserin. This compound was

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Figure 3. Piperazine-based 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as antidepressants.

Figure 4. Piperazine-based antidepressants reported by Gu et al..

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Figure 5. SAR studies of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acid derivatives.

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Figure 6. SAR studies of piperazine derivatives as MAO inhibitors.

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bulky group possess more affinity towards MAO B. Moreover, ylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine

Figure 7. SAR studies of 2-methoxyphenylpiperazine derivatives as antidepressants.

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antidepressant action of the compound is via action on 5-HT1A

Figure 11. LQFM104 and SAR of GSK-3β inhibitors of piperazine derivatives.

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Figure 13. SAR of piperazine derivatives of naphthyridine-3-carboxamides and indole-2-carboxamides possessing.

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Figure 14. SAR of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl and 7-tetrahydroisoquinolinyl-alkyl derivatives.

Figure 15. Various piperazine-based antidepressant compounds under development.

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Figure 16. SAR studies of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives.

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Kucwaj-Brysz et al. explored receptor–ligand interactions for

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Figure 20. SAR of N-(phenoxyalkyl)-, N-[2-[2-(phenoxy)ethoxy]ethyl]piperazine derivatives as antidepressants and PPMP.

Figure 21. SAR studies of arylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin.

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Figure 22. SAR studies of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives.

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Figure 23. SAR of piperazine bearing 6-acetyl-5-hydroxy-4,7dimethylcoumarin derivatives.

Figure 24. SAR of arylpiperazines bearing picolinamide.