C2 Drugs Acting on ANS.pptx

1
Medicinal Chemistry of
Drugs Acting on the Autonomic Nervous System
Part 1: Cholinergics, Anticholinesterases &
Cholinergic Antagonists
Part 2: Adrenergics and Adrenergic
antagonists

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Classification of the Nervous System

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Actions of the peripheral nervous system
Somatic
• Stimulation leads to the contraction of skeletal muscle
Autonomic
Sympathetic
• Contraction of cardiac muscle and an increase in heart rate.
• Relaxes smooth muscle and reduces the contractions of the GIT
and urinary tracts.
• Reduces salivation and dilation of the peripheral blood vessels.
• Fight or flight response of the body
Parasympathetic
• It leads to the opposite effects from those of the sympathetic
system.
• Rest and digest role of the body (house keeping role)
• Acetylcholine is released at the target organs and reacts
with receptors specific to it.

ANS has 2 sets of neurons:
1. Afferent (sensory) - sends impulses to the CNS for
interpretation (TO the CNS).
2. Efferent (motor) - receives impulses (info.) from the
brain & transmits from the spinal cord to the effecter
organ cells (FROM the CNS).

Overview of the ANS
• Drugs that stimulate the sympathetic nervous system
are called adrenergics [adrenergic agonists] or
[sympathomimetics]
– because they mimic the effects of the CNS neurotransmitters
norepinephrine and epinephrine (catecholamines).
• Adrenergic agonists – are drugs initiate a response
• Adrenergic antagonists – are drugs prevent a response
-Drugs that block = adrenergic blockers, sympatholytics or
adrenolytics
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• Drugs that stimulate the parasympathetic nervous
system are called cholinergics [cholinergic agonists or
parasympathomimetics]:
• B/s they mimic the effect of acetylcholine, which
responsible for the transmission of nerve impulses to
effector cells in the PSNS.
– Cholinergic agonists - initiates a response
– Cholinergic antagonists - prevents a response
- Drugs that block = anticholinergic, parasympatholytics
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NOREPINEPHRINE (NORADRENALINE) is the
principal neurotransmitter of postganglionic
neurons in the sympathetic nervous system;
neurons referred to as Andrenergic
ACETYLCHOLINE is the neurotransmitter of all
preganglionic fibers (both parasympathetic and
sympathetic).
Neurons that release acetylcholine are
referred to as CHOLINERGIC.
O
N+
O
OH
H
NH2
HO
HO
Neurotransmitters

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Nerve
Nerve
CHOLINERGIC NERVOUS SYSTEM/PSNS
1. Nerve Transmission
100-500A
Receptors
Release of
neurotransmitters
Receptor binding
and new signal
Nerve impulse
New signal
Vesicles containing
neurotransmitters
Synapses
Is Junction between two nerve cells (or with end-organ).

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2. Neurotransmitter
Acetylcholine (Ach)
Choline
Acetyl
innervates both smooth and cardiac muscle as well
as exocrine glands.

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Biologic responses to parasympathetic stimulation:
• Constriction of pupil (miosis), ciliary body
• Contraction of smooth muscle in the GI (“peristalsis”)
and urinary tract
• Constriction of the bronchioles (“bronchoconstriction”)
• Slowing of heart rate (“bradycardia”)
• Increased secretion by the glands

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Ach hydrolysed by acetylcholinesterase
Acetylcholine
H3C
C
O
O
Choline
+ NMe3
C
O
H3C OH
Acetic acid
NMe3
HO
Acetylcholinesterase (AChE), a serine hydrolase enzyme, is responsible
for the hydrolysis of acetylcholine to form choline and acetate.
E 1
Choline
+ CH2 NMe3
CH2
HO
C
O
H3C SCoA
Acetylcholine
H3C
C
O
O
NMe3
E1 = Choline acetyltransferase

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• Acetylcholine is synthesized in the nerve ending of the pre-
synaptic nerve from choline and acetyl CoA.
• The reaction is catalysed by the enzyme choline -
acetyltransferase, E1.

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3. Cholinergic receptors
Receptor types
• Two types of cholinergic receptor-
• nicotinic (Na+-channels) on skeletal muscles and at nerve synapses;
• muscarinic (G-protein-coupled) on smooth and cardiac muscles
• Named after natural products showing receptor selectivity
Acetylcholine is natural messenger for both receptor types
Activates cholinergic
receptors at nerve synapses
and on skeletal muscle
Activates cholinergic
receptors on smooth
muscle and cardiac muscle
N
N
nicotine
O
H3C CH2NMe3
HO
muscarine

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Design, physicochemical and clinical
properties of Drugs Acting on ANS
Drugs Acting on PSNS Can be classified into:
• Cholinergic agonists
• Cholinergic antagonists

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How can we develop a drug to have acetylcholine like effects?
Agonize the
acetylcholine
receptors
Prevent the fast
metabolism of
acetylcholine by
acetylcholinesterase
Enhance ACh release
AGONIST ACTIVITY

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4. Cholinergic agonists
4.1 Acetylcholine as an agonist
Advantages
• Natural messenger
• Easily synthesised
Disadvantages
• Poorly absorbed across biological membranes
• Easily hydrolysed in stomach (acid catalysed hydrolysis)
• Easily hydrolysed in blood (esterases)
Ac2O
NMe3
+
O HO NMe3 NMe3
AcO
• ACETYLCHOLINE has an important role as a chemical
neurotransmitter.
O
N+
O

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4. Cholinergic agonists…
4.2 Nicotine and muscarine as cholinergic agonists
Advantages
• More stable than Ach
• Selective for main cholinergic receptor types
• Selective for different organs
Disadvantages
• Activate receptors for other chemical messengers
• Side effects

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4. Cholinergic agonists…
4.3 Requirements for cholinergic agonists
• Stability to stomach acids and esterases
• Selectivity for cholinergic receptors
• Selectivity between muscarinic and nicotinic receptors

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Acetoxy
Ethylene
bridge
4 o Nitrogen
Me O
NMe3
O
Acetoxy
Ethylene
bridge
Nitrogen
Me O
NMe3
O
5. SAR for acetylcholine
Quaternary nitrogen is essential
Bad for activity
O
CMe3
H3C
O
O
NMe2
H3C
O

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Muscarinic selective agonists
• Treatment of glaucoma (reducing intraocular pressure by outflow
of aqueous humor)
• Switching on GIT and urinary tract after surgery (reestablish
smooth muscle tone in GI and urinary tracts)
• Treatment of certain heart defects (Decreases heart muscle
activity and decreases heart rate.)
Nicotinic agonists
• Treatment of myasthenia gravis.
Therapeutic Indications

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Acetylcholinesterase inhibitors (AchEI)
or anticholinesterases
 Anti-cholinesterase drugs stop the enzyme from
hydrolyzing acetylcholine
 This antagonism can be
 Reversible
 Irreversible
 There are two main groups of acetylcholinesterase
inhibitors
i. Carbamates
ii. Organophosphorus agents

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Reversible inhibitors of acetylcholinesterase Carbamates
N
N
O
O
NH
Physiostigmine
• Treatment of glaucoma
• Antidote anticholingeric agents (tricyclic antidepressants or atropine)
• For treatment of cognitive disorders (Alzheimer’s disease)
• Antidote for atropine poisoning
SAR
• The carbamate group is essential to
activity
• The benzene ring is important
• The pyrrolidine nitrogen (which is
ionized at blood pH) is important

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Analogs of Physiostigmine:
• They are orally available; commonly used to treat myasthenia
gravis
NMe3
O NMe2
O
N
Me
O NMe2
O
Neostigmine
Pyridostigmine
O N
H
O
Me
Me2N
Me
Miotine

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Irreversible inhibitors of acetylcholinesterase
How to increase half-life?
Increase stability of acylated enzyme: phosphate esters
• AChE is inhibited irreversibly by a group of phosphate
esters that are highly toxic.
• These chemicals are nerve poisons and have been used in
bioterrorism, and as agricultural insecticides.
P
A
X
R1
R2
O, S, Se
alkoxy
good
leaving
group
alkoxy
or alkyl

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IRREVERSIBLE INHIBITORS OF ACETYLCHOLINESTERASE
Isoflurophate (Floropryl ®) Echothiophate Iodide (Phospholine ®)
O P
O
O
F
O
P
O
O
S
N
+
I-
Topical ointment when other agents fail
Can last for up to 4 weeks
(increase selectivity by addition
of quaternary nitrogen)

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IRREVERSIBLE INHIBITORS OF ACETYLCHOLINESTERASE
O
P
S
O N
+
O
-
O
O
O
P
S S
O
O
O
O
O
parathion malathion
• There are no metabolic pathways in mammals, which can
convert the phosphorus -sulfur double bond to a
phosphorus- oxygen double bond.
• Such pathway does, however, exist in insects.
• parathion and malathion act as prodrugs.
• They are metabolized by oxidative desulfuration to give the
anticholinesterases, which irreversibly bind to the insects’
acetylcholinesterases enzymes and lead to death

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Cholinergic antagonist
Cholinergic antagonist: Agents that produce biological activity
opposite to the PSNS stimulation
- prevent the biosynthesis or release of Ach
- bind to acetylcholine receptors but exhibit no
intrinsic activity
 “parasympatholytic.”
Cholinergic antagonists
 Muscarinic Antagonists
 Nicotinic Antagonists

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Cholinergic Antagonists (Muscarinic receptor)
• Agents with high binding affinity for cholinergic receptors
but no intrinsic activity.
• Prevent acetylcholine from binding
• Lower activity of acetylcholine
• Opposite clinical effect to agonists
Anticholinergics/Antimuscarinics
(Receptor Blockers)

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Clinical Effects
• Decrease of saliva and gastric secretions (antisecretary)
• Relaxation of smooth muscle
• Decrease in motility of GIT and urinary tract
(antispasmodic)
• Dilation of pupils (mydriatic effect)
Therapeutic Uses:
• Shutting down digestion for surgery
• Ophthalmic examinations
• Relief of peptic ulcers
• Anticholinesterase poisoning
• Motion sickness
• Common in flu/cold remedies (reduce nasal secretions)

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Atropine
• Racemic form of hyoscyamine
• Competitive (reversible) antagonist of ACh
• Source - roots of belladonna (1831)
• Used as a poison,,,,, + cosmotic
• Used as a medicine
-decreases GIT motility
-antidote for anticholinesterase poisoning
-dilation of eye pupils
• CNS side effects - hallucinations
*
N
H
O
C
O
Me
CH
CH2OH
easily racemised
THE PROTOTYPE ANTICHOLINERGIC

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Hyoscine (scopolamine)
• Source - thorn apple
• Medical use - treatment of motion sickness
• Used as a truth drug (CNS effects)
*
N
H
O
C
O
Me
CH
CH2OH
O
H
H

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SAR for Antagonists
Important features
• The nitrogen can be tertiary or quaternary, whereas agonists must have
quaternary nitrogen
• N-Alkyl groups (R) can be larger than methyl (unlike agonists)
• Ester
• R’ = aromatic or heteroaromatic ring
R2N
CH2
CH2
O
C
O
CH
R'
R'
R' = Aromatic or
Heteroaromatic

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•Tertiary amine (ionised)
or quaternary nitrogen
•Aromatic ring
•Ester
•N-Alkyl groups (R) can be
larger than methyl
R’ = aromatic or heteroaromatic
Branching of Ar rings important
•Quaternary nitrogen
•Methyl group
•Ester
•N-Alkyl groups = methyl
R’ = H
SAR for Antagonists SAR for Agonists
SAR for Antagonists vs Agonists
Pharmacophore = ester + basic amine + aromatic ring
R2N
CH2
CH2
O
C
O
CH
R'
R'

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Simplified Analogues
Pharmacophore = ester + basic amine + aromatic ring
Amprotropine
N
CH2
CH2
CH2
O
C
O
Et
CH
CH2OH
Et
Tridihexethyl bromide
HO C CH2CH2N(Et)3 Br
Propantheline chloride
Cl
O C
O
O CH2CH2 N
CH
Me
CH
Me Me
Me
Me

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Simplified Analogues
Tropicamide
(opthalmics)
Cyclopentolate
(opthalmics)
Benztropine
(Parkinsons disease)
Benzhexol
(Parkinsons disease)
Pirenzepine
(anti-ulcer)
CH
CH2OH
O
N
CH2CH3
N
N
H
O
CH
Me
N
CH
N N
C
HN
C O
CH2
N
N
O
Me
CH
O
O
OH
Me2N

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Regarding the synthetic agents are:
• Very Muscarinic selective
• drugs with tertiary nitrogen show limited nicotinic
antagonist activity
• Available orally or by IV; treat ulcers and where one
wants reduced motility of GI tract
• Tertiary nitrogen drugs are well absorbed and
distributed
• Those drugs with amino ether or amino alcohols
cross blood-brain barrier (Parkinson’s disease)

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Cholinergic Antagonists (Nicotinic receptor)
Two classes:
-- skeletal neuromuscular blocking agents
-- ganglionic blocking agents
-All therapeutically useful nicotinic antagonists
are competitive inhibitors whose effects are
reversed by ACh
NICOTINIC ANTAGONISTS

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Curare
• Used as arrow poison
• Causes paralysis (blocks acetylcholine signals to muscles)
• Active principle = tubocurarine
Neuromuscular blocking agents
N
+
H
OH
O
O
N
+
H
H
O
O
O
H
SAR: two quaternary ammonium salts separated
by 10-12 carbons
Why? Nicotinic receptor has two anionic binding
sites!

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Pharmacophore
• Two quaternary centres at specific separation (1.15nm)
• Different mechanism of action from atropine based antagonists
• Different binding interactions
Clinical uses
• Neuromuscular blocker for surgical operations
• Permits lower and safer levels of general anaesthetic
• Tubocurarine used as neuromuscular blocker but has side
effects

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Part 2: Adrenergics and adrenergic
antagonists
The Adrenergic System:
– sympathetic nervous system
– In fight or flight situations
– the concentration of adrenaline may increase 1000-fold in a
matter of seconds.
– The target tissues here are: liver, skeletal muscles, heart and
vascular system.
• The neurotransmitters active are
norepinephrine (noradrenaline) and
epinephrine (adrenaline).

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NOREPINEPHRINE (NORADRENALINE) is the principal
neurotransmitter of postganglionic neurons in the
sympathetic nervous system; neurons referred to as
ADRENERGIC
OH
H
NH2
HO
HO
CATECHOLAMINE
ortho-dihydroxybenzene

43
OH
H
NH2
HO
HO
OH
H
NH
HO
HO
ISOPROTERENOL
NOREPINEPHRINE
OH
H
NH2
HO
HO
OH
H
NH
HO
HO
EPINEPHRINE
a: epinephrine > norepinephrine > isoproterenol
b: isoproterenol > epinephrine > norepinephrine
Adrenergic receptor types
…as with the muscarinic/nicotinic receptors, there are multiple
adrenergic receptor types: alpha and beta
Sub types a1 (mainly post synaptic), a2 (mainly presynaptic)
b1, b2, b3, …

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Physicochemical and clinical properties of transmitters
Physicochemical properties
• Catecholamines
(acidic vs basic)
• Prone to oxidation
• Optically active
• Possible binding
interactions
OH
H
NH2
HO
HO
OH
H
NH
HO
HO
NOREPINEPHRINE
EPINEPHRINE

46
NOREPINEPHRINE
OH
H
NH2
HO
HO
OH
H
NH
HO
HO
EPINEPHRINE
…far more widely used clinically.
--- IV only due to rapid metabolism (liver COMT, MAO)
Similar uses to Norepinephrine and…
b2 activity leads to use by IV and in inhalers for broncho-
constriction in asthma (and for inhibiting uterine contractions)
a activity had led to use in nasal decongestants (by constriction
of dilated blood vessels in mucous membranes) but after-
congestion limits utility
~equal activity at
both a & b, b1 & b2
-- treat allergic reactions
-- treat shock
-- prolong local anesthetic action
~equal activity
at both a & b1,
less at b2
(light sensitive; if discolored, do not use)
…has limited clinical application because of the
--- po ineffective
--- non-selective nature of its action (v.c & cardiac stimulation).
--- IV only due to rapid metabolism (liver COMT, MAO)
--- Duration of action 1-2 minutes, even when infused
•Used to counteract hypotensive crises (because a activity raises
blood pressure)
•Adjunct treatment in cardiac arrest where the b activity
stimulates the heart.

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Adrenergic agonist SAR
1. Agonists must have the phenylethylamine parent structure (circled)
2. Dihydroxy at 3’, 4’ is preferred. Removal of 4’—OH leaves only a activity.
Removal of 3’—OH produces b-selectivity. 3’,5’-substituted compounds are
resistant to COMT, have better oral bioavailability and are b -selective.
3. Benzylic carbon (1) must be in R configuration. Most common therapies are
racemates.
4. Small substituents are tolerated at the 2 position and increase MAO
resistance.
5. The nitrogen is either 10or 20 .The activity at a and b-receptors is maximal
when R1 is methyl as in epinephrine, but a-agonist activity is dramatically
decreased when R1 is larger than the methyl and is negligible when R1 is
isopropyl, as in isoproternol leaving only b-activity
overview
OH
H
NH2
HO
HO
H
N
R2
OH
R1
1
2
R3
2'
3'
4'
5'
6'

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6. As R1 becomes larger than butyl, affinity for a1-receptor returns but not
intrinsic activity, which means large lipophilic groups can afford
compounds with a1-blocking activity
7. N- substituent can also provide selectivity for b-receptors.
E.g. T-butyl group selectivity for b2 –receptors
Colterol (R1= t-butyl) is a selective b2-agonist, whereas isoproterenol is a
non-selective b-agonist.
8. Substitution like methyl or ethyl group at a- to basic Nitrogen, Carbon-2
slow metabolism by monoamine oxidase (MAO) but has little overall
effect on duration of action in cathecolamines because they remain
substrates for COMT.
9. An ethyl group in this position diminishes a-activity far more than b-
activity, affording compounds with b-selectivity such as
ethylnorepinephrine.
10. The natural 3’,4’-dihydroxy substituted benzene ring present in
norepinephrine provides excellent receptor activity for both a and b-
sites. Both such cathecol-containing compounds have poor oral activity
because they are hydrophilic and rapidly metabolized by COMT.
11. 3’,5’-dihydroxy compounds are not good substrates for COMT and in
addition show selectivity for b2-receptors. Eg. Metoproterenol

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a1 adrenergic agonists: PHENYLETHANOLAMINES
Phenylephrine
Methoxamine
(bioactivated to phenol)
Metaraminol
OH
NH2
HO
OH
NH
HO
OH
NH2
O
O
…as discussed, removal of
4-OH reduces a-activity but
nearly abolishes b-activity
Not substrates for COMT
hence duration of action is
longer than NE. Used for
treating hypotension during
surgery or shock
Also used as nasal
decongestant (both
orally and topically)
and ocular
decongestant
High dose Methoxamine (due to b-activity) and Phenylephrine (due to
increasing blood pressure) have been used to treat arrhythmias
NOTE: most b-agonists are phenylethanolamines!!!
…a activity is reduced, but b is almost eliminated

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Adrenergic agonist SAR
OH
H
NH2
HO
HO
1
2
3’
4’
5’
5. The nitrogen is either 10or 20 . Larger substitutions of the N provide b-
selectivity (i.e. t-butyl as an R group is highly b2 selective). Bulky N
substituents significantly reduce a-activity.
OH
H
NH
O
H
OH
4’-OH retains
b activity
Bulky sustituent
provides b2 selectivity
Inhibits MAO,
increasing to ethyl
would give even more b
activity
Ritodrine
b2 agonists

C2 Drugs Acting on ANS.pptx

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