5.7 : Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship

Cholinergic agonists or cholinomimetics mimic the action of acetylcholine to stimulate the parasympathetic nervous system. They are categorized into direct-acting and indirect-acting agents. The direct-acting cholinergic drugs induce the parasympathetic response by directly binding to the muscarinic or nicotine receptors. In comparison, the indirect-acting cholinergic drugs prevent acetylcholine hydrolysis, indirectly contributing to the extended parasympathetic response.

The direct-acting cholinergic agonists comprise naturally occurring plant alkaloids and synthetic choline esters. Examples of naturally occurring alkaloids include pilocarpine, arecoline, and muscarine. Pilocarpine is the chief alkaloid found in the genus of Pilocarpus shrubs in South America, while muscarine was first isolated from the mushroom Amanita muscaria. Arecoline is found in the areca nut of the palm Areca catechu. Synthetic choline esters include methacholine, carbachol, and bethanechol.

Choline esters possess structural attributes that make them resistant to enzymatic hydrolysis by acetylcholinesterase, thereby prolonging their effects compared to acetylcholine. Carbachol, containing a carbamoyl group, contributes to the higher specificity for nicotinic receptors and comparatively lower affinity for muscarinic receptors. However, carbachol exhibits increased resistance to acetylcholinesterase hydrolysis. In contrast, methacholine, with a methyl group, exhibits higher muscarinic activity and lower nicotinic activity, and it is slowly hydrolyzed by the enzyme. On the other hand, bethanechol, which contains both carbamoyl and methyl groups, only has muscarinic activity and is highly resistant to enzymatic hydrolysis.