What are Cholinergics/Parasympathomimetics?

    Drugs which produce actions similar to that of ACh, either by directly interacting with cholinergic receptors (cholinergic agonists) or by increasing availability of ACh at these sites (anticholinesterases).

General Structure


SAR of Cholinergic Drugs

1. Onium ion group [Quaternary Ammonium group]

Onium group is essential for intrinsic activity and contributes to the affinity of the molecule for the receptors, partially through the binding energy and partially because of its action as a detecting and directing group.

Trimethylammonium group is the optimal functional moiety for activity, although some significant exceptions are known (e.g., pilocarpine, arecoline, nicotine, and oxotremorine).

Phosphonium, sulfonium, arsenonium isosteres, or substituents larger than methyl on the nitrogen increase the size of the onium moiety, produce diffusion of the positive charge, and interfere sterically with proper drug–receptor interaction, resulting in decreased activity.

2. Ethylene Bridge [Choline Moiety]

Shortening or lengthening the chain of atoms that separates the ester group from the onium moiety reduces muscarinic activity.

        An alpha substitution on the choline moiety decreases both nicotinic and muscarinic activity, but muscarinic activity is decreased to a greater extent.

        Nicotinic activity is decreased to a greater degree by substitution on the beta carbon.

Nicotinic activity decrease due to beta substitution

"Alpha – Muscarinic  decreased
Beta – Nicotinic decreased"

        Beta substitution decreases hydrolysis by AchE than alpha substitution.

3. Ester Function

        The ester group contributes to the binding of the compound to the muscarinic receptor because of hydrogen bond formation with threonine and asparagine residues at the receptor site. 

        Replacement of methyl group by ethyl or large alkyl groups produces inactive compounds.