1. Review Position of Hydrogen on a Chiral Carbon
Aromaticity and Special Nitrogens in Rings

2. CHOLINERGIC DRUGS Cholinergic Drugs
These are agents that interact with receptors utilizing the neurotransmitter (NT) acetylcholine (ACh).
Cholinergic Synaptic Sites
autonomic effector sites: innervated by post-ganglionic parasympathetic fibers
autonomic ganglia and the adrenal medulla
some CNS synapses
skeletal muscle neuromuscular junction (motor nerves)
Terminology
The term mimetic is applied to agents that activate and lytic is applied to those that block the actions of NT receptors.
Thus, cholinergic agonists are often referred to as parasympathomimetics or cholinomimetics while antagonists are referred to as parasympatholytics or cholinolytics.

3. RECEPTOR TYPES NICOTINIC RECEPTORS
There are 2 main subtypes of cholinergic receptors
Nicotinic (N) and Muscarinic (M)
NICOTINIC RECEPTORS
There are at least 2 subtypes N1 and N2
The N1 receptor is found at the neuromuscular junction where its activation results in skeletal muscle contraction
The N1 receptors are blocked by d-tubocurarine, succinylcholine and decamethonium
The N2 receptors are found at the autonomic ganglia and are blocked by hexamethonium and trimethaphan
MUSCARINIC RECEPTORS
Currently there are 5 subtypes; M1 – M5
The muscarinic receptors are blocked by Atropine

4. Acetylcholine Biosynthesis and Effect of ACh on the Cholinergic System
Ca2+
Na+
Muscarinic
Receptor
ACH
Choline
Acetyltransferase (CHAT)
Acetylcholinesterase
Acetyl CoA +
Acetylcholine
Action Potential
Choline a b
Na+ H+
Nicotinic
Receptor
ACH
Choline
Acetate
Choline
Presynaptic neuron
Postsynaptic target

5. Interaction of Acetylcholine at Muscarinic Receptors
Tyr381 VI I
VII
Thr189 V II IV
III
Asp105

6. Pharmacological Effects of Cholinergic Agonists
Ophthalmic Effects
Miosis
Cardiovascular Effects
Negative chronotropic Effects
Negative inotropism (decreased contractility)
Decreased SA and AV nodal conduction velocity
Effect on ionic currents
Gastrointestinal and Urinary Tract Effects
Secretion of gastric acid, intestinal peristalsis, tone, and contraction amplitude. Stimulate urinary tract by increasing ureteral peristalsis

7. STRUCTURE ACTIVITY RELATIONSHIP (SAR)
ONIUM GROUP
1) Essential for intrinsic activity, contributes to affinity as well.
2) Optimal functional group for activity
3) Increase in size of methyl groups (on N) decrease activity
ESTER GROUP
1) Contributes to binding affinity
2) Acetyl group not critical for activity and can be replaced
3) The single bonded oxygen appears to be important for high muscarinic activity.
CHAIN
1) shortening or lengthening of chain decreases activity.
2) a - substitution decreases M activity more than it does nicotinic activity.
3) b - substitution decreases N activity more than it does M activity.

8. Individual Direct-Acting Cholinergic Agents
Predict the selectivity of the following compounds at M and N receptors
Individual Direct-Acting Cholinergic Agents
Acetylcholine Chloride
- Cardiac depressant and vasodilator
- Bronchial constriction
- Skeletal muscle contraction
- Stimulates secretions from salivary and sweat glands
- atropine blocks M effects but not those of N receptors
PROBLEM: ACh is easily hydrolyzed by acetyl cholinesterase (AChE). In addition, an aq solution of ACh is unstable, thus prepare solution just before use.

9. What can we do to decrease the ease of hydrolysis of acetylcholine?
Less easily hydrolyzed Less easily hydrolyzed
Possess the same pharmacology as Ach Selective for M receptors
Pilocarpine (Diocarpine, Miocarpine)
Non-selective muscarinic agonist
It has a 3S, 4R stereochemistry
Used in the treatment of open angle glaucoma

10. Indirect Acting Cholinergic Drugs
Two common enzymes hydrolyze ACh
1) Acetylcholinesterase (AChE)
Compounds which inhibit AChE prolong the life of ACh, thus they produce similar effects as direct agonist.
2) Butyrylcholinesterase / Pseudocholinesterase ( BuChE )
- located in human plasma
- biologic functions unknown
-hydrolyzes a broader group of esters (AChE hydrolyzes only acetyl & propionyl gps )

11. Replacement of the Ester Functional Group
Three different functional groups interact with the esteratic site in AChE
Ester Inhibition: Is completely reversible
Carbamate Inhibition: Is semi-reversible
Effective carbamylation is in the order shown below. Why?
Organophosphate Ester Inhibition
AChE inhibition by organophosphate results in phosphorylation which is irreversible

12. REVERSIBLE AChE INHIBITORS
1. PHYSOSTIGMINE (Eserine) - NATURAL PROD
Functional groups include: carbamate ester, pyrrolidine.
Arrange the N atoms in physostigmine according to their pKas.
NEOSTIGMINE BROMIDE ( PROSTIGMINE )
Carbamate ester, quaternary ammonium salt
Dimethyl group provides more chemical stability than
monomethyl or H
Can be given orally and pH has no effect on activity. Why?
Used in Myasthenia gravis to prevent atony of skeletal and GI musculature.
( Myasthenia gravis is a degenerative neuromuscular disease)
3. PYRIDOSTIGMINE BROMIDE ( MESTINON )
less toxic than Neostigmine
most widely used anti-AChE agent to treat MG 

13. REVERSIBLE AChE INHIBITORS (Contd)
4. AMBENONIUM CHLORIDE (Mytelase)
Used in the treatment of MG Is poorly absorbed from GI ( why ? )
Is not hydrolyzed by Cholinesterases Metabolism: unknown
5. DEMECARIUM BROMIDE ( HUMORSOL )
Aqueous solution is stable
Long acting miotic
Used to treat wide angle glaucoma. 
6. EDROPHONIUM CHLORIDE ( TENSILONON )
An anticholinesterase without the carbamate functional group
Therefore, does not react with the receptor.
Often used as a potential diagnostic agent for MG

14. IRREVERSIBLE AChE INHIBITORS
ORGANOPHOSPHATE ESTER INHIBITORS
Used as both drugs and nerve poisons
Used also as agricultural insecticides
Long lasting anticholinesterase
When A=S, referred to as a Phosphothionate and
must be metabolized to the active compound by desulfuration.
MOA: Bind irreversibly to AChE or BuChE
ISOFLUOROPHATE (Floropryl)
Irreversible inhibitor of AChE and effect can last for days or even weeks.
Decomposes in water but stable in oil
Can be absorbed readily through the skin.
Is used clinically in the treatment of glaucoma.
ECHOTHIOPHATE ( Phospholine )
Unlike isofluorophate when used topically it is not
readily absorbed, thus has limited in vivo distribution
used in the treatment of glaucoma.

15. IRREVERSIBLE AChE INHIBITORS
INSECTICIDES
MALATHION
Insoluble in water
Rapidly hydrolyzed in mammals
to inactive metabolite.
But undergoes desulfuration in insects
to form an active metabolite.
PARATHION (Thiophos)
Low volatility with a stable
aq solution – More polar
Probably the cause of most common
accidental OP poisoning and death.

16. Antidote for Organophosphate Poisoning
Pralidoxime chloride ( Protopam, 2 - PAM)
Serves as antidote for irreversible anti AChE
Serves as effective antagonist for some carbamates such as neostigmine & pyridostigmine bromide.
Little or no effect if not used before 36h of poisoning because of aging
Phosphorylation of AChE
Mechanism of Reversing Phosphorylation: Require the use of a better nucleophile

17. Newer Anticholinesterase Agents
Rivastigmin Tartrate (Exelon®)
Centrally selective and long-lasting anticholinestarase activity
Is a pseudo-irreversible carbamate AChE inhibitor (Inhibits the enzyme
for as long as 10 h due to slow dissociation.)
Also shows selectivity for AChE as compared to BuChE.
Donepezil (Aricept®)
Is a reversible non-competitive inhibitor of AChE.
About 1000X more selective for AChE than BuChE
shows greater affinity for brain over peripheral AChE..
Slows down the loss of cognitive functions and hence is used in Alzheimer’s disease.
Readily penetrates the CNS and is 100% bioavailable by mouth.

18. CHOLINERGIC BLOCKING AGENTS
1. Postglanglionic parasympathetic nerve terminals in smooth muscles –
blocked by Atropine
2. Autonomic ganglia: - blocked by hexamethonium
3. Neuromuscular junction: - blocked by d - tubocurarine
We will now consider #1 also referred to as parasympatholytics, cholinolytics,
antimuscarinic (block muscarinic receptors)
CLINICAL SIGNIFICANCE OF ANTICHOLINERGICS
1) improve cardiac rate output (used in bradycardia )
2) lower motility of GI tract (antispasmodic effect)
3) reduce salivation, perspiration, acid & gastric secretions (antisecretory effect)
4) produce dilation of the pupil of the eye (mydriatic effect )
GENERAL MECHANISM OF ACTION:
- occupy AChR and prevent ACh from binding to the receptor
-These compounds have some component of ACh, with additional (often bulky groups)
that extend beyond receptor area occupied by ACh & impart affinity.

19. STRUCTURE-ACTIVITY RELATIONSHIP
ANTIMUSCARINIC PHARMACOPHORE
A; B = Bulky groups such as
Aromatic or cycloalkyl groups,
D = H, -OH, CONH2
CATIONIC HEAD: A positively charged N atom either as quaternary ammonium salt,
or becomes positively charged at physiological pH
cationic head improves affinity but does not appear to be absolutely necessary.
HYDROXYL GROUP ( OH )
- enhances affinity but is not a requisite for activity.
- appears to be involved in H-bonding to an electron rich center on the receptor
ESTER GROUP ( COOR)
present in many potent molecules but is not necessary for the activity.
CYCLIC SUBSTITUENTS: At least one cyclic substituent (phenyl, cyclohexyl, etc) is present in
most compounds. Substituents on the ring do not contribute to activity.
STEREOCHEMICAL REQUIREMENTS
Alcohol Portion: only small differences between R & S isomers.
Acid Portion: shows significant differences
CONNECTING CHAIN : Usually a 2-carbon chain

20. CHOLINERGIC BLOCKING AGENTS
A AMINO ALCOHOL ESTERS.
a) ATROPINE: Is a naturally occurring alkaloid
--Standard anticholinergic agent
b) CYCLOPENTOLATE ( CYCLOGYL )
- 1/2 as active as Atropine
c) DICYCLOMINE ( BENTYL )
-used 1oly for spasmolytic effect on various
smooth muscle spasms especially those of GI origin.
d) GLYCOPYRROLATE ( ROBINUL )
- used as an adjunct in the management of peptic ulcer
and other GI ailments associated with hyperacidity,
hypermotility and spasm.
- Little or no CNS effect ( why ?)
- high doses can block ganglia & myoneural junction.

21. CHOLINERGIC BLOCKING AGENTS
B. AMINOALCOHOL ETHERS
a) BENZTROPINE (Cogentin)
-Useful in Parkinsonism because of its anticholinergic properties
-Relieves tremors, rigidity associated with Parkinsonism
-Has sedative properties as well
b) CHLORPHENOXAMINE HYDROCHLORIDE (Phenoxene)
Due to presence of Cl and CH3 gps, this drug has reduced
antihistamine effect but has increased anticholinergic action.
Useful in the symptomatic treatment of Parkinson’s disease

22. CHOLINERGIC BLOCKING AGENTS
C. AMINOALCOHOLS a) TRIHEXYPHENIDYL HYDROCHLORIDE (ARTANE) Notice the presence of the piperidine ring - 1/2 antispasmodic action as atropine - useful in the treatment of Parkinson’s Disease D. AMINOAMIDES a) ISOPROPAMIDE IODIDE ( DARBID ) - only slightly soluble in H2O ( why? ) - long duration of action - used in adjunctive therapy in the treatment of peptic ulcer, and other GI ailments E. DIAMINES a) ETHOPROPAZINE ( PARSIDOL ) - Has a phenothiazine ring system - useful in the symptomatic treatment of Parkinson’s disease - common side effects include drowsiness and dizziness.