Authonomic NS

UNIT TWO
Medicinal chemistry of Drugs Acting on the
Autonomic Nervous System
By Yabibal Berie (B. Pharm, MSc)

Yabibal B. Tadesse 1
Outlines
• Introduction to Central Nervous System
• Neurotransmitters of ANS
• Synthesis and metabolism of Neurotransmitters of
ANS
• Cholinergic and adrenergic receptors
• Cholinergic and adrenergic analogues and agonists
• Antagonists of ANS
• Diseases treated by ANS agents
Introduction
• Based on the anatomic origin of out flow
– Divided in to two
1. Sympathetic division
– Come from thoracic and lumber regions of the spinal cord
– Is the “Fight or Flight” branch of the ANS
» Increases Cardiac output and Pulmonary ventilation
» Directs blood to muscles
» Raises blood glucose
» Slows down digestion, kidney filtration & other functions
not needed during emergencies
Autonomic Nervous System cont.
2. Parasympathetic divisions
– Comes from cranial & sacral regions of the CNS
– Is the “Rest & Digest” branch of the ANS
» Promotes normal maintenance of the body
» Involved in urination, defecation & getting rid of the
wastes
» Promotes secretion & mobility of different parts of the
digestive tract
• Sympathetic & Parasympathetic systems often
function in antagonistic ways
Fight or flight vs. rest and digest
Anatomy of ANS
• The two systems (Sympathetic &
parasympathetic) use
– The same neurotransmitter in the ganglia (ACh)
– Quite different neurotransmitters are used at the
organs
• Parasympathetic  Acetylcholine
• Sympathetic  Norepinephrine (noradrenaline)
Classification of neurons
• Adrenergic neurons
– Produce norepinephrine as principal
neurotransmitter
• In postganglionic neurons of the sympathetic
nervous system
• Cholinergic neurons
– Produce acetylcholine as neurotransmitter in all
• Preganglionic fibers of the ANS (both
sympathetic & parasympathetic)
– Postganglionic fibers of the parasympathetic
division and in the exceptions of the sympathetic
division
Classification of neurons cont.
H
OH
O
HO NH2
+
N(CH3)3Cl-
H3C O
Acetylcholince chloride HO
R(-)-Norepinephrine
Synthesis & release of ACh from the cholinergic
neurons
• Neurotransmission in cholinergic neurons involves 6 steps.
1. Synthesis-> in the nerve terminal from acetyl-coenzyme A &

Choline
2. Storage-> stored in synaptic vesicles
3. Release-> to the synapse
4. Binding of the Ach to a receptor-> binds to the cholinergic receptor
and leads to biological response within the cell
5. Degradation of the ACH->acetylcholinesterase (AChE) breaks it
down into acetate and choline
6. Recycling of choline->backYabibal
intoB.the
Tadesse
presynaptic neurons for 11
Synthesis & release of ACh from the cholinergic
neurons......
cholinergic receptors
1. Muscarinic receptors
• They’re located postsynaptically on smooth muscle and
cardiac muscle
• It is named “muscarinic” because it can be stimulated by
the alkaloid muscarine
• they’re G-Protein coupled receptors
• Muscarinic receptor contains 5 sub-types: M1, M2, M3,
M4 & M5. H
HO
H
H
N+(CH3)3Cl-
O
H3C
Muscarine chloride
cholinergic receptors cont.
2. Nicotinic receptors
• are located in the ganglia of both the Parasympathetic
and Sympathetic nervous system.
• It is named “nicotinic” because it can be stimulated by
the alkaloid nicotine.
• Ion channel receptors that activates Na+ channel
• Nicotinic receptor contains 2 sub-types: N1 (NM) & N2
(NN)
N
nicotine
Acetylcholine (ACH)
• ACH is a prototypical muscarinic and nicotinic agonist &
neurotransmitter in the ANS.
• An imbalance in the parasympathetic tone leads to serious illness.
• If there is a lack of ACH acting at a certain part of the body, can
we just administer more ACH? (conceptually YES!) WHY?
There are three reasons why this is not feasible.
• ACH is easily hydrolysed in the stomach by acid catalysis and
cannot be given orally.
ACH...
• ACH is easily hydrolysed in the blood by
esterase enzymes (esterases).
• There is no selectivity of action.
– Therefore, we need analogues of ACH that
are more stable to hydrolysis and more
selective with respect to where they act in the
body
Acetylcholine receptor binding
• There is H-bonding interactions exist b/n the ester group of ACH and an asparagine residue.
• Hydrophobic pocket exists which can accommodate the methyl group of the ester
• The N+Me3 group is placed in a hydrophobic pocket lined with 3 aromatic amino acids.
• It is also thought that the pocket contains two smaller hydrophobic pockets, which are large
enough to accommodate two of the three methyl substituents on the N +Me3 group.
• The 3rd methyl substituent on the N is positioned in an open region of the binding site.
• A strong ionic interaction has been proposed between the charged nitrogen atom and the
anionic side group of an aspartate residue.
Structural Activity Relationship (SAR)
 The positively charged nitrogen atom is essential to activity. Replacing it
with a neutral carbon atom eliminates activity.
 The distance from the nitrogen to the ester group is important.
 The ester functional group is important.
 The ethylene bridge between the ester and the nitrogen atom cannot be
extended
 There must be two methyl groups on the nitrogen. A larger, third alkyl group
is tolerated, but more than one large alkyl group leads to loss of activity.
 Bigger ester groups lead to a loss of activity.
Structural activity relationship cont.
We concluded that
• Only compounds possessing a positive charge on the atom in the position
of the nitrogen had appreciable muscarinic activity
• Replacing all the three methyl groups on the nitrogen by larger alkyl
groups leads to loss of agonist activity
• When the three methyl groups are replaced by ethyl groups
– The resulting compound is a cholinergic antagonist
• Replacement of only one methyl group by ethyl or propyl group
– Affords an active compound
• But much less active than ACH
• Successive replacement of one, two or three methyl groups with hydrogen
atoms
– Affords a tertiary, secondary or primary amine
• Leading to successively diminishing muscarinic activity
O
+
N(CH3)3
H3C O
Design of ACH Analogues
There are two possible approaches to tackling the inherent instability of
acetylcholine:
1. Steric shields: by adding extra methyl group on the ethylene bridge as a steric
shield to protect the carbonyl group, thus slowing down chemical and
enzymatic hydrolysis.
2. Electronic stabilization: by replacing acyl methyl group with NH2 which means
that the ester has been replaced by carbamate group. This functional group is
more resistant to hydrolysis because the lone pair of electrons on nitrogen can
interact with the neighbouring carbonyl group and lower its electrophilic
character.
O
+
N(CH3)3
H3C O
1. Modification of the ethylene group
• There should be no more than five atoms
– Between the N & the terminal hydrogen atom for
maximal activity
• Replacement of H atoms of the ethylene bridge
– By alkyl groups larger than methyl
• Affords compounds much less active than
ACH
O
+
N(CH3)3
H3C O
1. Modification of the ethylene group.....
• Introduction of a methyl group on the carbon  to the 40

Nitrogen
– Affords acetyl- -methylcholine (methacholine)
• Is selective for muscarinic receptors
• Has muscarinic potency equivalent to that of ACH
• Possesses much greater muscarinic potency than
nicotinic potency
• A methyl group on the carbon -to the 40 nitrogen
– Affords acetyl -methylcholine
• Relative to ACH, activity is reduced at both muscarinic
& nicotinic receptors
– It exhibits greater nicotinic than muscarinic potency
Modification of the ethylene group cont…
O
O CH3
N(CH3)3 Cl
N(CH3)3 Cl H3C O
H3C O
CH3
Acetyl- -methylcholine chloride
Acetyl--methylcholine chloride
2. Modification of the acyloxy group
• Chemical instability of ACH can be solved by
– Replacing the acetyloxy group with a functional group resistant to
hydrolysis
– Lead to the synthesis of carbamic acid ester of choline
• A potent cholinergic agonist - Carbachol
– Possessing both muscarinic & nicotinic activity
– Less readily hydrolyzed in the GIT or by AChE
» Can be administered orally
• Replacing the acetyl group by propionyl or butyryl---The resulting ester is less potent than ACH
• Choline esters of Aromatic or high mol. wt. acids
• Possess cholinergic antagonist activity
N(CH3)3 Cl
H2N O
Carbachol
3. Modification of the acyloxy and
etheylene groups
O
N(CH3)3 Cl
H2N O
Carbachol
• We have seen that the β-methyl group of methacholine increases stability and
introduces receptor selectivity.
• Therefore, it made sense to add a β-methyl group to carbachol.
• The resulting compound is bethanechol which is both stable to hydrolysis and
selective in its action.
• It is occasionally used therapeutically in stimulating the GIT and urinary bladder
after surgery and it is used clinically for the treatment of glaucoma where it can be
applied locally. O CH3
N(CH3)3 Cl
H2N O
Bethanechol
Cholinergic drugs
• Are drugs that mimic the effects of acetylcholine

• Can be classified into two groups
1. True or direct cholinergic drugs
• Drugs whose qualitative mode of action is the same
as that of ACH (Choline esters)
• e.g. Pilocarpine
Cont....
– False or indirect cholinergic drugs
• Inhibit the hydrolysis of ACH by AChE
– Eg. Physiostigmine
Acetylcholine esterase inhibitors (AChEI’s)
• In the parasympathetic nervous system action

of ACH is terminated by
– Its rapid acetylcholine esterase (AChE) catalyzed
hydrolysis
• To acetic acid and choline
• Inhibition of AChE
– Increases concentration of ACH in the synapse
• Results in production of both muscarinic & nicotinic
responses
Acetylcholine esterase inhibitors cont.
N(CH3)3
H3C O
H2O, AChE
O CH3
H3C OH
+ HO
N(CH3)3
Therapeutic applications of AChEI’s
• AChE inhibitors also called anticholinesterases
– Are classified as indirect cholinomimetics
• B/s principal mechanism does not involve binding to
cholinergic receptors
• Used therapeutically
– To improve muscle strength in myasthenia gravis
– To treat glaucoma
– To treat symptoms of Alzheimer's disease & similar
cognitive disorders
– Other conditions characterized by cholinergic
deficiency in the cortex & basal forebrain
– Also used as insecticides & in chemical warfare
1. Reversible inhibitors of AChE
• Are substrates for & react with AChE
– To form an acylated enzyme which is more stable than the acetylated enzyme
• But still capable of undergoing hydrolytic regeneration
– Or
• Bind to AChE with greater affinity than ACH
– But do not react with the enzyme as substrate
• Clinically useful inhibitors are those of the first type & include
– Aryl carbamates
• Esters of carbamic acid & phenols such as physiostigmine
– Alkyl carbamates
• Esters of carbamic acid and alcohols such as carbachol and bethanechol
• Aryl carbamates & Alkyl carbamates are structurally related to ACH
– Are substrates for AChE
– Competitively inhibit AChE
– Are hydrolyzed very slowly by water
Structure of AChE inhibitors
O
Me O
Me
O
N
N(CH3)3
H2N O
H
N N
Carbachol
Urethane Me Me
or
Carbamate
Physiostigmine
O CH3
N(CH3)3
H2N O
Bethanechol
Mechanism of AchE
Mechanistic steps in hydrolysis of Ach
O
OH
AChE-Se-OH +
N(CH3)3
N(CH3)3
H3C H3C O
O
A O-Ser-AChE
B
O
O
H2O +
N(CH3)3
H3C OH HO
H3C O-Ser-AChE
+ C (inactive)
AChE-Ser-OH
Aryl carbamate AChE inhibitors
• When aryl carbamate AChE inhibitors
– Such as physiostigmine and its analogues bind to
the catalytic site of AChE
• Hydrolysis of carbamate occurs
– Which trans esterifies the serine residue with carbamic acid
» To give the carbamylated enzyme
H2N O-Ser-AchE Carbamylated AchE
Aryl carbamate AChE inhibitors cont.
• Regeneration of active AChE by hydrolysis of
the carbamylated AChE
– Much slower than hydrolysis of the acetylated
enzyme
O
O
H2O
H2N O-Ser-AchE
+ AchE-Ser-OH
Carbamylated AchE H2N OH
CO2 + HNR2
2. Irreversible inhibitors of AChE
• Are substrates for AChE
– Result in an acylated enzyme
• More stable to hydrolysis than a carboxylate
• Phosphate esters are very stable to hydrolysis
– Are more stable than many amides
• Act as inhibitors by the same mechanism as the
carbamate inhibitors
– Except that they leave the enzyme esterified as phosphate ester
Irreversible inhibitors of AChE cont.
• Important feature of irreversible phosphoester

derived AChEIs
– Can undergo a process known as aging
• Aging plays an important role in the toxicity of
these irreversible AChEIs
O O O
Aging Aging
AchE-Ser-O P OR AchE-Ser-O P O AchE-Ser-O P O
OR OR O
Aging
• Organophosphates inactivate AChE by
phosphorylating the serine hydroxyl group
located at the active site of AChE.
• Over a period of time, phosphorylation is
followed by loss of an organophosphate
leaving group and the bond with AChE
becomes irreversible, a process known as
aging.
Carbamylation vs phosphorylation
Aging by Phosphate compounds
Examples of irreversible AChEIs
• Therapeutically important ones
– Diisopropylflurophosate & Echothiophate iodide
(phospholine)
• Because of their toxicity, not used for their systemic
action
– Have topical therapeutic application for the treatment of
glaucoma
» Decrease in intraocular pressure they cause can last up to 4 weeks
O O N+(CH3)3I-
H3C CH3
O P O H3CH2CO P S
H3C CH3
F OCH2CH3
Diisopropylfluorophosphate (DFP) Echothiophate iodide
Insecticidal AChEIs
• Many lipophilic derivatives of phosphoester
AChEIs designed as insecticides
– Are beneficial in agriculture worldwide
O
S S O
H3CO P S OCH2CH3
H3CH2CO P O NO2 H3CH2CO P O NO2
OCH3 OCH2CH3 OCH2CH3 OCH2CH3
Malathion O Parathion Paraoxon
Cl O O
S O
H3C
H3CH2CO P O Cl (H3C)2N P O P N(CH3)2 O P F
OCH2CH3 H3C CH3
Dichlorfenthion
N(CH3)2 N(CH3)2 Sarin
Schradan
Insecticidal AChEIs cont.
• These insecticidal compounds
– Are extremely electrophilic
– Have high vapor pressure
• Hence should be used with caution to avoid
– Absorption through the skin
– Inhalation of the vapor
» Number of fatal poisonings reported every year
– Those having a sulfur atom on phosphorous with coordinate covalent
bond
• As such exhibit little AChEI activity
• But are rapidly bioactivated by microsomal oxidation in insects
– To afford the corresponding oxo derivatives (phosphate esters) which are very
potent
S O
H3CH2CO P O NO2 Bioactivation H3CH2CO P O NO2
OCH2CH3 OCH2CH3
Parathion Paraoxon
Antidote for irreversible AChEIs
• Hydroxyl amine (NH2OH) is a strong nucleophilic compound
– Can efficiently cleave phosphate esters
– Significantly increase rate of hydrolysis of phosphorylated AChE
• But at concentration that is toxic
• Would be logical to design a compound with
– High degree of selectivity to AChE
– Strong binding affinity for AChE
– Carry a hydroxyl amine like nucleophile into close proximity to the phosphorylated serine residue
• 2-pyridine aldoxime methyl chloride (pralidoxime) is the only drug with
such activity
N
HO
N Cl
H
CH3
Pralidoxime chloride (2-PAM)
Reactivation of AChE with 2-PAM
O
(2-pyridine aldoxime methyl)
N
+ OH
AchE-Ser-O-P-(OR)2
N
H O
CH3
AchE-Ser O P (OR)2
H O N
N
O
H CH3
PAM O P (OR)2 + AchE-Ser.OH
H
Mechanism of 2-PAM
Anticholinergics
Muscarinic antagonists
• Commonly referred to as
– Anticholinergics, antimuscarinics, cholinergic blockers,
parasympatholytics
• Have high binding affinity for muscarinic receptors
– But no intrinsic activity
• Antagonists bind to receptors to produce no response
• Act as competitive antagonists of ACH
– Having pharmacologic effects opposite that of muscarinic agonists
• Responses of muscarinic antagonists include
– Decreased contraction of smooth muscle of GIT & urinary tract
– Dilation of the pupils
– Reduction of gastric secretion
– Decreased secretion of saliva
Anticholinergics cont.
Muscarinic antagonists
• Have therapeutic value in treating
– Smooth muscle spasm
– reduced saliva and gastric secretions
– Gastric ulcer
– In ophthalmic examinations
– To reduce nasal & upper respiratory tract secretions
• Earliest known anticholinergic agents are alkaloids (atropine,
scopolamine, etc.) from
– Atropa belladona
– Hyoscyamus niger
– Datura stramonium
• Atropine is the tropic acid ester of tropine
– The naturally occurring alkaloid is (-)-hyoscyamine
– Atropine gets formed during extraction by base catalyzed racemization
• Scopolamine is the generic name given to (-)-hyoscine, the naturally
occurring alkaloid
– It has been used in the treatment of motion
sickness.
CH3
CH3
N
N
O H
H CH2OH
CH2OH
H
O CH
O CH H 
*
O
O
Atropine / (+)-hyoscyamine Hyoscine / Scopolamine

• Atropine is the prototype anticholinergic agent
– It provided the structural model that guided the design and synthesis
– Circled portion depicts segment resembling ACH
• In atropine
– Amine group separated from the ester by more than two carbons
• But conformation assumed by tropanol ring orients these two atoms at a distance similar to that
of ACH
• One important structural difference between atropine & ACH that are both esters of
amino alcohols
– Is the size of the acyl portion of the molecule
• Most potent ones are those possessing two lipophilic rings on the carbon -to the carbonyl of
the ester moiety
O
H
N-CH3 O C C
H2C
OH
Structural analogues based on atropine
• Both atropine and hyoscine are tertiary amines rather than
quaternary salts
– Thus are able to cross the blood brain barrier
• Antagonize muscarinic receptors in the brain leading to CNS effects like
– Hallucinogenic effects at high dose
– Restlessness
– Agitation
– Hyperactivity
• Disorienting effects of scopolamine made it useful as
– Truth drug for the interrogation of spies
• To reduce CNS side effects
– Quaternary salts of atropine are often used clinically
• Ipratropium as a bronchodilator
• Atropine methonitrate to lower motility of the GIT
Structural analogues based on atropine cont.
CH(CH3)2 CH3
Br NO3
N N
H3C H3C
H H
CH2OH CH2OH
O CH O CH
* *
O O
Ipratropium Atropine methonitrate
Structural analogues based on atropine cont.
• Important groups while synthesizing analogues of atropine are

– The basic nitrogen
• An important binding group and interacts in the ionic form
– The aromatic ring
– The ester group
– Complex ring system of atropine may not be necessary for antagonistic activity
• Studies showed that
– Alkyl groups on nitrogen could be larger than methyl
– The nitrogen can be tertiary or quaternary in antagonists
• Agonists must have a quaternary one
– Very large acyl groups are allowed
• Aromatic or heteroaromatic rings
– There must be some sort of branching in the acyl group
H2 R'
C O CH
R2N C R' R' = Aromatic or heteroaromatic
H2
O
General structure of muscarinic antagonists
Synthetic cholinergic blockers
Efforts to use antispasmodic effects of atropine often results in
– Dryness of the mouth
– Fluctuations in pulse rate
• Synthesis of compounds with similar action but decreased side
effects was essential
– This lead to the development of
• Aminoalcohols
• Aminoalcohol esters
Synthetic cholinergic blockers cont.
• Aminoalcohols
– Are similar to the classic anticholinergic cpd s
derived from atropine
• Have antiparkinsonian property
– Need to have a tertiary nitrogen to pass BBB
– Quaternization of these amino alcohols has been
utilized to enhance
• Antispasmodic & antisecretory activities
CH2CH2 C2H5
N
C CH2CH2 N C2H5 Cl
OH
C2H5
H2C
OH
Yabibal B. Tadesse Tridihexethyl chloride 56

Biperiden
antispasmodic & antisecretory
Useful in Parkinson's syndrome
Synthetic cholinergic blockers cont.
• Aminoamides
– Represent the same type of molecule as the amino alcohols
• With the important exception that the polar amide group
– Replaces the corresponding polar hydroxyl group
– Isopropamide iodide is the only drug of this class currently in use
• Produces atropine like effects
– Provide antispasmodic and antisecretory effects for as long as 12hrs
C2H5
I
CH2CH2 N C2H5
C2H5
C NH2
Isopropamide iodide
Nicotinic antagonists
• Nicotinic receptors present in
– Nerve synapses at ganglia
– The neuromuscular synapse
• Antagonists of the ganglionic nicotinic receptor sites are not
useful therapeutically
– Can’t distinguish between ganglia of
• Sympathetic and parasympathetic nervous system
– Consequently have many side effects
• Neuromuscular blockers are therapeutically useful
– Nicotinic antagonists
• Chemical compounds that bind to nicotinic receptors but with no efficacy
The neuromuscular junction
59
Yabibal B. Tadesse
The neuromuscular junction
• Ach is essential for muscle contraction
• MOA: Voltage dependent Ca2+ gates (channels) open and Ca2+
enters the axon terminal.
– Calcium influx causes the release (exocytosis of vesicles) of
acetylcholine into the synaptic cleft
• Acetylcholine (ACh) binds to ACh receptors on the post-
synaptic terminal (muscle cell)
• Ion channels open and Na+ flows into the muscle cell and K+
flows out
• The membrane is depolarised (excited) and this depolarisation
spreads down the T tubules, initiating contraction
• ACh dissociates from the receptor
• Acetylcholinesterase in the cleft breaks down the ACh
60
Yabibal B. Tadesse
Nicotinic antagonists cont.
• Therapeutically useful nicotinic antagonists are
competitive antagonists
– i.e. effects are reversible with ACH
• Tubocurarine is the first known neuromuscular
blocking agent
– Is important to the understanding of nicotinic antagonists as
atropine was to muscarinic antagonists
• Therapeutically useful compounds in this group also
referred to as drugs with
– Curariform
– Curarimimetic activity
• we sometimes call them Nondepolarizing blocking agents

Nondepolarizing blocking agents…
• Non-depolarizing blockers compete with
acetylcholine for receptors.
• Depolarizing agents cause prolonged stimulation and
subsequent desensitization of the receptors.
• Nondepolarizing neuromuscular blockers can be
classified into two classes based on their chemical
structure:
• Steroidal (eg, rocuronium, vecuronium,
pancuronium) or benzylisoquinoline (eg,
mivacurium, atracurium, cisatracurium).
Neuromuscular blocking agents
• Term traditionally applied to drugs that compete with
– ACH for the recognition site on the nicotinic receptor
• By preventing depolarization of the end plate by the neurotransmitter
• Thus, by decreasing the effective ACH-receptors combination
– The end plate potential becomes too small
» To initiate the propagated action potential
• Compounds in this class can have one or two 4 0 ammonium
groups
• Structure of this compound serves as a scaffold
– To position the two positive charges in the correct three dimensional
orientation
• For interaction with trans membrane nicotinic receptors
Neuromuscular blocking (Nondepolarizing blocking) agents
• Reaction of d-tubocurarine with CH3I affords metocurine iodide
– In which the two phenolic OH groups of tubocurarine are changed to methyl
ether
– The tertiary amine becomes quaternary
• Metocurine is about X4 more active than tubocurarine in neuromuscular blocking
activity
I
H3C R RO OCH3
H3CO O H3C
CH3
RO d-tubocurarine iodide (R=H)

Metocurine iodide (R=CH3)
Steroid based neuromuscular blocking agents
O
O C CH3
CH3
R2
CH3 H
R1
H H
R3 O O
H H3C
Pancuronium R1 = R2 = N
R3 = CH3
O
H3C
Vecuronium R1 = R2 = N R3 =
N CH3
CH3 O
Pipecuronium R1 = R2 = N N R3 =
CH3
CH3
N
Rocuronium R1 = N O R2 = H
R3 =
Steroid based neuromuscular blocking agents cont.
• Pancuronium
– Is a long acting agent
– May cause an increase in heart rate and BP
• Should not be used in patients with coronary artery
diseases
– Undergoes hydrolysis in the liver
• To the active 3-hydroxy metabolite and
• The inactive17-hydroxy and 3,17-dihydroxy
metabolites
• Is primarily excreted in the urine
• Vecuronium
– Removal of the methyl group from the quaternary
piperidine group at position 2 of pancuronium
gives vecuronium
– An intermediate acting drug
Depolarizing blocking agents (nicotinic
agonist)
• Drugs in this category are known to bring about
– Depolarization of the membrane of the muscle
end plate
• This depolarization is similar to that produced by ACH
– At ganglia & neuromuscular junction
» So known as nicotinic effect
• Smooth or voluntary muscle when challenged
repeatedly with a depolarizing agent eventually
become insensitive
– A phenomenon known as tachyphylaxis or desensitization
making the plates insensitive to ACH in a few minutes
Specific depolarizing neuromuscular blockers
• Decamethonium bromide
– SAR study on a series of bis-quaternary ammonium compounds
– With varying number of methyl groups separating the nitrogen atoms
was done
• Maximal neuromuscular blockage was observed with 10 to 12
unsubstituted methylene groups
• Activity diminishes as number of methylene groups increases or decreases
from the optimum number
• Compound with six methylene groups (hexamethonium) is a nicotinic
antagonist at autonomic ganglia  Ganglionic blocking agent
(CH3)3N+ (CH2)10 N+(CH3)3

Br- Br-
Specific depolarizing neuromuscular blockers cont.
• Succinylcholine
– Represents two molecules of acetylcholine
• Connected at the carbons  to the carbonyl of the acetic acid moiety
– Is rapidly hydrolyzed & rendered inactive both in plasma and aqueous
solutions by esterases
• This chemical property makes it of brief duration of action
– Thus used for rapid & short duration of neuromuscular blockage
O N(CH2)3 Cl
O
N(CH3)3 Cl
Adrenergic agents
Adrenergic agents (also known as sympathomimetics) are
drugs that mimic or block the action of norepinephrine and
epinephrine at postganglionic synapses of the sympathetic
nervous system, and in the CNS.
Adrenergic agents…
Adrenergic Neurotransmitters
– Adrenergic nerves release the neurotransmitters Norepinephrine
(NE), Epinephrine (E) & Dopamine (D).
– NE is released from sympathetic nerve ending into the synaptic
cleft where it reacts with specific presynaptic & postsynaptic
adrenergic receptors
– but epinephrine is not released from peripheral sympathetic nerve
endings as in NE rather synthesized & stored in the adrenal
medulla
Adrenergic agents…
Norepinephrine & epinephrine
– both are endogenous adrenergic agonists.
– Are members of a class of pharmacologically
active substances known as catecholamines
• Because they contain with in their structure
–Both an amine and meta dihydroxy
benzene (catechol)
HO RHN
R = H; Norepinephrin
HO R = CH3; Epinephrin
Yabibal B.
OH Tadesse 72
Biosynthesis, storage & release of NE
• Biosynthesis of NE takes place with in drenergic neurons
near the terminus of the axon
• NE is biosynthesized in a presynaptic neuron then stored in
membrane-bound vesicles.
• Biosynthesis begins with the active transport of L-
tyrosine into adrenergic cell
• L-tyrosine-->L-dopa-->dopamine-->NE--
>Norepinephrine
Reuptake & metabolism
• Following its release, NE diffuses through the

intracellular space
– To bind reversibly to adrenoceptors (,)
• On the effecter cells triggering a biochemical cascade
– Resulting in physiologic response
there are two mechanism for termination of the action of NE:
Uptake 1:when the NE diffusion away from the synapse & metabolism at the
postsynaptic area
Uptake 2: is an extraneuronal uptake process when the NE is attached at the
presynaptic area of the nerve terminal.
– catecholamines (NE and E) are metabolized by Monoamine oxidase

(MAO) & Catechol-O-methyltransferase (COMT) enzymes.
– MAO converts NE into aldehydes, whereas COMT catalyses the methylation
of one of the phenolic groups of the NE (catecholamines)
Metabolism of NE
H H OH H OH
H OH OH
HO NH2 MAO HO O HO O MeO O
COMT
H OH OH
HO HO HO HO
Noradrenaline Vanillylmandelic acid
OH H OH
H H OH
H OH MeO NH2 MeO O MeO O
HO NH2 COMT MAO
H OH
HO HO HO
HO
Vanillylmandelic acid
Noradrenaline
Adrenergic Receptors (Adrenoreceptors)
• Adrenergic receptors were classified as  & 
– Based on their responses to different adrenergic
agonists
• Norepinephrine
• Epinephrine
• Isoproterenol
• Those designated as  (Alpha) are stimulated by
these agonists
– Epinephrine ≥ Norepinephrine >> Isoproterenol
– Alpha has two subtypes (α1 and α2)
– could be either presynaptic or postsynaptic &
excitatory or inhibitory in their responses
Adrenoreceptors....
• Those designated as  (Beta) get stimulated in
the order
– Isoproterenol > epinephrine >
norepinephrine
– has three subtypes (β1, β2 & β3)
– All are postsynaptic & excitatory
– Presynaptic receptors
• α2-adrenoceptor interacts with released NE
and has an inhibitory effect on further release of NE
Location & Function of adrenergic receptors
Organ responding Major receptor type Response
Ateriols 1 Constriction
2 Dilation
Vascular smooth muscle 2 Dilation
Eye (radial muscle) 1 Contraction (papillary
dilation)
Fat cells , lipolysis
Heart 1 Increase rate & force
Increased conduction velocity
Intestine ,  Decreased motility
Liver , 2 Increased gluconeogenesis

and glycogenolysis
Lungs 2 Relaxation (bronchial dilation)
Uterus 1 Contraction (In pregnant women)

2 Relaxation
Adrenergic receptor binding site & NE
Structure–activity relationships (SAR) of
Adrenergic agents
R2 substituent on the amino nitrogen
• Increase in size from

– Hydrogen  methyl  isopropyl
– Norepinephrine  epinephrine 
isoproterenol
• Activity at -receptor decreases (?) and
• Activity at -receptors increases
• Activity at  & -receptors is maximal
when R2 is methyl as in epinephrine
• -agonist activity is dramatically
decreased when R1 is larger than methyl
Cont’
• N- substituent can also provide
selectivity for -receptors
– E.g. T-butyl group (Colterol) 
selective for 2-receptors (agonist)
– Isoproterenol is a nonselective -
agonist
• When considering use as a bronchodilator
– Nonselective -agonists such as isoproterenol has
undesirable cardiac stimulatory effects
R2 substituent on the amino nitrogen cont.
OH
OH H
HO N
HO NH2
HO
HO
Isoproterenol
Norepinephrine A non selective-agonist
OH
OH H
HO N
H
HO N CH3
HO
HO Colterol
Epinephrine A selective 2 agonist
R substituent -to basic nitrogen (carbon-2)
• An ethyl group in this position
– Diminishes -activity more than -activity
– Affords compounds with -selectivity
• E.g. ethyl norepinephrine
OH
OH HO NH2
1'
6' NH R2
2' 1
2
HO
3' 5' R
Ethylnorepinephrine
4'
OH
1'
Phenol substitution on the aromatic ring 2'

6'
1
2
NH R2
3' 5' R
4'
• The natural 3’,4’-dihydroxy substituted benzene ring

in norepinephrine
– Provides excellent receptor activity for both  & -sites
• Such catechol containing compounds have poor oral
activity because
– They are hydrophilic & rapidly get metabolized by COMT
• Alternative substitution have been found
– That retain good activity &
– Render resistance to COMT metabolism
Phenol substitution on the aromatic ring cont.
OH
H OH
HO N H
HO N
CH3
Phenylephrin
OH Metoproterinol
OH CH3
H OH
N CH3
HO NH2
CH3
HO
CH3
OH Albuterol
Metaraminol
Catecolamine Adrenergic Agonists
Norepinephrine & adrenergic drugs
• NE has limited clinical application
– It is nonselective
– Given only intravenously
• Due to metabolism by intestinal & liver
COMT & MAO
– Low lipophilicity
– Rapid metabolism limits its duration of
action
• Only 1-2min given by infusion
Norepinephrine & adrenergic drugs......
• NE administered
– To counteract hypotensive crises and cardiac arrest
• Epinephrine is more widely used clinically than NE
– Although it lacks oral activity for the same reason
as NE it is used to
• Treat hypotensive crisis
• Stimulate the heart in cardiac arrest (due to its
greater -activity)
• Given i.v. to inhibit uterine contraction
• In form of inhalers to relieve
bronchoconstriction in asthma
-Adrenergic agonists
α1 agonists
1. Phenylethanolamines
• Include Metaraminol, methoxamine, and
phenylephrine
• Have longer duration of action
• Their α1-agonist activity makes them strong

vasoconstrictors.
-Adrenergic agonists cont.
2. Arylimidazolines
• Contain a one carbon bridge b/n C2 of imidazole ring & a
phenyl substituent
– Therefore the general skeleton of ethanolamine is contained with in the
structure
• Are selective 1 agonists with vasoconstrictor and vasopressor
activity
• Are widely used only in topical preparations as nasal decongestants and
eye drops CH 3
H
CH
H
3
N HO N
H3C H3C
N N
CH3 CH3
H3C H3C
CH3 CH3
Xylometazoline Oxyometazoline
α2 agonists
Clonidine
• was originally synthesized as a

vasoconstricting nasal decongestant but Cl
H
it was found to have dramatic N N
hypotensive effects
HN
• Clonidine penetrates the BBB and
Cl
interact with central nervous system clonidine
α2-receptors.
-adrenergic agonists
B1-agonists
Dobutamine
OH
H
–Is a dopamine analogue with bulky HO N
aryl alkyl group on the nitrogen and HO

Dobutamine
has one chiral center.
• Acts receptor B1 receptor-agonist

-adrenergic agonists....
2-agonist
• Most -selective adrenergic agonists used primarily as
– Bronchodilators in asthma & other constrictive pulmonary
conditions
• Examples are
– Albuterol, Pirbuterol, Terbutaline
» Are non-catechol 2 selective agonists
» Can be used orally
OH OH
H H
N N N
HO HO
Pirbuterol OH Albuterol
OH Yabibal B. Tadesse 94
Mixed acting sympathomimetics
Ephedrine
• Is a natural product isolated from several species of the genus Ephedra
• Does not have any substituents on the phenyl ring
– It is orally active as it is not a substrate for COMT
• Lacking hydrogen bonding phenyl substituents
– It is less polar and can easily cross BBB compared to catechols
• Isomer with 1R, 2S absolute configuration has
– Direct activity on the receptors, both  & 
– Also has an indirect component
OH
NHCH3
* *
Ephedrine (1R:2S &)
Pseudoephedrine (1R:2R & 1S:2S) * Chairal centers
CH3
Four isomers of Ephedrine
CH3 CH3 CH3 CH3
H C NHCH3 H3CHN C H H C NHCH3 H3CHN C H

H C OH HO H HO C H H OH
(-)-Ephedrine (+)-Ephedrine (+)-Pseudoephedrine (-)-Pseudoephedrine
Mixed acting sympathomimetics
Methyl substituted phenylethylamines
• S(+)Amphetamine and S(+)Methamphetamine
– Both lack ring substituents and side chain hydroxyl
groups
• Are sufficiently lipophilic to cross the BBB
– Cause dramatic CNS stimulation
» Are drugs of abuse
H
NH2 N CH3
* *
CH3 CH3
Amphetamine Methamphetamin
Adrenoreceptor Blocking Agents
• Adrenergic blocking agents are drugs that selectively inhibit
specific receptor sites from sympathetic stimulation.
• There are several modes of action, which over all result in a
depression of adrenergic nerves.
• The blocking agents may interact with specific alpha and beta
receptors as a result the release of NE from storage sites may be
blocked and its storage may be inhibited. Drugs in this category
are mostly antihypertensive agents.
• Depression of adrenergic nerves results in a vasodilation effect
and relieves high BP causedYabibal
by B.aTadesse
constriction of the capillaries. 98
Adrenoreceptor Blocking Agents...
• Clinical uses:
 Anti-hypertensive
 To treat cardiac failure
 In prostatic hyperplasia
• Selective α1-Antagonists
 There are 3 agents which contain quinazoline core structure and
highly selective α1-rcceptor antagonists. These are Prazosin,
Terazosin & Doxazosin

• SAR of Quinazoline
• The 4-amino group on the quinazoline ring is very
important for a1 –receptor affinity.
• Piperazine ring replaced with other heterocyclic moieties
(e.g.. piperidine) without loss of affinity.
• Acyl group has a significant effect on the pharmacokinetic
properties
• Reduction of the furan to a THF increases duration of
action
• These agents use in the treatment of benign prostatic
hyperplasia (BPH) and HTN.
• Tamsulosin (1-Antagonist)
• It is aryl sulfonamide derivative
• Blocked of 1 receptors in prostate.
• It is approved for treatment of benign prostatic hyperplasia

-Adrenoreceptor Antagonists
• Isoprenaline was chosen as the lead compound, althoughit is an

agonist.
• Replacing the phenolic groups of Isoprenaline with chloro substituents
produced dichloroisoprenaline (DCI) . This compound was a partial
agonist, but has no clinical importance.
• The chloro groups of dichloroisoprenaline were replaced by an extra
benzene ring to give a naphthalene ring system( pronethalol ) was still
a partial agonist.

-Adrenoreceptor Antagonists…
• SAR of -Adrenoreceptor Antagonists
• Introduction of oxymethylene bridge (-OCH2) between the
naphthalene ring and the ethanolamine portion of the pronethalol to
prepare the structure now known propranolol
• In general the aryloxy propanolamines are more potent β-
receptor blockers than the corresponding arylethanolamines
• Propranolol was found to be a pure antagonist, having 10–20 times
greater activity than pronethalol.

-Adrenoreceptor Antagonists…
• Since the development of propranolol a large number of
additional β-blockers have been brought to market.
• They have various side effects, such as:-bronchoconstriction,
reduced cardiacoutput &CNS effects. B/c they block non-
selectively all β-receptors

• 1-receptor antagonists
• A new series of 4-substituted phenyloxypropanolamines emerged
such as atenolol, betaxolol, metoprolol & acebutolol are 1-receptor
antagonists.
• They inhibit sympathetic cardiac stimulation and have no effect on
lung muscles 2 receptors

General α-/β-blockers
• Carvedilol and labetalol are agents which act as antagonists at both

the α− and β- adrenoceptor
• They have unusual activity in that they are
• antihypertensive with α1 , β1, β2 blocking activity
• They have both been used as antihypertensive and
carvedilol has been used to treat cardiac failure.

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UNIT TWO

Medicinal chemistry of Drugs Acting on the

Autonomic Nervous System

By Yabibal Berie (B. Pharm, MSc)

1. Synthesis-> in the nerve terminal from acetyl-coenzyme A &

• Introduction of a methyl group on the carbon  to the 40

• Are drugs that mimic the effects of acetylcholine

• In the parasympathetic nervous system action

H2N O-Ser-AchE Carbamylated AchE

• Important feature of irreversible phosphoester

Diisopropylfluorophosphate (DFP) Echothiophate iodide

Malathion O Parathion Paraoxon

Pralidoxime chloride (2-PAM)

Atropine / (+)-hyoscyamine Hyoscine / Scopolamine

Ipratropium Atropine methonitrate

• Important groups while synthesizing analogues of atropine are

Yabibal B. Tadesse Tridihexethyl chloride 56

• we sometimes call them Nondepolarizing blocking agents

RO d-tubocurarine iodide (R=H)

(CH3)3N+ (CH2)10 N+(CH3)3

• Following its release, NE diffuses through the

– catecholamines (NE and E) are metabolized by Monoamine oxidase

Liver , 2 Increased gluconeogenesis

Uterus 1 Contraction (In pregnant women)

• Increase in size from

Phenol substitution on the aromatic ring 2'

• The natural 3’,4’-dihydroxy substituted benzene ring

• Their α1-agonist activity makes them strong

• was originally synthesized as a

aryl alkyl group on the nitrogen and HO

has one chiral center.

• Acts receptor B1 receptor-agonist

CH3 CH3 CH3 CH3

H C NHCH3 H3CHN C H H C NHCH3 H3CHN C H

(-)-Ephedrine (+)-Ephedrine (+)-Pseudoephedrine (-)-Pseudoephedrine

Yabibal B. Tadesse 100

• It is aryl sulfonamide derivative

• Blocked of 1 receptors in prostate.

• It is approved for treatment of benign prostatic hyperplasia

Yabibal B. Tadesse 102

• Isoprenaline was chosen as the lead compound, althoughit is an

Yabibal B. Tadesse 103

Yabibal B. Tadesse 104

Yabibal B. Tadesse 105

Yabibal B. Tadesse 106

• Carvedilol and labetalol are agents which act as antagonists at both

• antihypertensive with α1 , β1, β2 blocking activity

• They have both been used as antihypertensive and

carvedilol has been used to treat cardiac failure.

Yabibal B. Tadesse 107

Yabibal B. Tadesse 108

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