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.
Cholinergic agonists mimic the actions of ACh, and such cholinomimetics are either direct- or indirect-acting agents.
Direct-acting agonists bind to and activate both muscarinic and nicotinic receptors and induce a response longer than ACh.
They are categorized as—choline esters and their synthetic derivatives and naturally occurring alkaloids.
ACh—the endogenous choline ester, features an ethylene bridge linking a charged quaternary ammonium to an ester group, facilitating ACh binding to the receptor.
The ester group is, however, susceptible to AChE enzyme, which hydrolyzes ACh and terminates its action.
Synthetic choline esters are derived from ACh. They have subtype selectivity and are resistant to enzymatic hydrolysis. Presence of an additional –CH3 group in the linker imparts enhanced selectivity for muscarinic receptors.
Naturally occurring alkaloids include tertiary and quaternary amines, which exhibit receptor specificity and are unaffected by AChE enzyme.
繁體中文
