[MEDORG-SEMIS-04-PT4] CHOLINERGIC

THIS FLASHCARDS IS ABOUT [MEDORG] CHOLINERGIC - CORE SAR FRAMEWORK.

Acetylcholine scaffold

All cholinergic drugs are modifications of the?

Supplemental Info Only

Start with the acetylcholine structure, then explain how each modification produces a different drug class.

Basic scaffold: (CH3)3N+ — CH2 — CH2 — O — C(=O) — CH3

(Four regions determine activity)

Positively charged nitrogen

QUATERNARY AMMONIUM GROUP:

Role: The _____________________ binds to the muscarinic receptor.

Supplemental Info Only

IMPORTANT RULES:

• Small groups → agonist activity

• Bulky groups → antagonist activity

EXAMPLE LOGIC:

• Acetylcholine → agonist

• Atropine → antagonist (bulky groups)

Increasing steric bulk converts agonists into antagonists.

Two carbon atoms

(Changing the distance reduces receptor binding)

What is the optimal spacing between nitrogen and ester?

(N⁺ — CH2 — CH2 — O)

• Acetylcholine

• Bethanechol

• Methacholine

The spacing appears in (3)?

Hint: ABM

(It is a key pharmacophore rule)

Metabolic stability

The ester determines?

Acetylcholine

This is rapidly hydrolyzed by acetylcholinesterase.

Carbamate substitution

What is the medicinal chemistry solution of ester functional group?

Bethanechol

What is an example of drug that has ester functional group?

Supplemental Info Only

ESTER FUNCTIONAL GROUP’S EFFECTS:

• Resistant to enzymatic hydrolysis

• Longer duration of action

(Carbamate substitution increases drug stability)

Methyl group

BETA-CARBON SUBSTITUTION:

Adding a _____________ on the B-carbon produces important changes.

Example: Methacholine

Effects:

• Increased muscarinic selectivity

• Decreased nicotinic activity

• Slower hydrolysis

(β-methyl substitution improves muscarinic selectivity)

B-methyl group

What is the modification of methacholine?

More muscarinic selectivity

What is the result of methacholine?

• B-methyl group

• Carbamate ester

What are the modifications of bethanechol (2)?

• Resistant to acetylcholinesterase

• Longer duration

What are the results for bethanechol (2)?

Large bulky groups replace small substituents

What is the modification of atropine?

Muscarinic antagonist

What is the result for atropine?

Quaternary ammonium

What is the modification of ipratropium?

• Limited CNS penetration

• Local bronchodilation

What are the results of Ipratropium (2)?

Supplemental Info Only

All cholinergic drugs are acetylcholine molecules modified to control receptor selectivity, metabolic stability, and tissue distribution.