5.19 : Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

Cholinergic antagonists bind to cholinergic receptors and limit the effects of acetylcholine and other cholinergic agonists. Based on the specific cholinergic receptor affinity, these antagonists are classified as muscarinic or nicotinic. Anticholinergics interrupt parasympathetic innervations while sympathetic innervations remain uninterrupted. Muscarinic antagonists are also called 'muscarinic antagonists', 'antimuscarinics', or 'parasympatholytics'. Nicotinic antagonists are called 'neuromuscular blockers' and 'ganglionic blockers'.

Antimuscarinics are classified into three groups based on their source. First are the naturally occurring alkaloids, which include atropine and scopolamine. Second are the semisynthetic derivatives of these natural alkaloids, such as homatropine, hyoscine, and ipratropium. They differ from their parent compounds in their duration of action and pharmacokinetics. Third are synthetic compounds such as tropicamide, oxybutynin, and procyclidine. Synthetic derivatives show receptor specificity to the different muscarinic receptors.

Most anticholinergics consist of an ester group and a basic nitrogen group separated by a carbon linker. An intact ester group is essential for potent anticholinergic activity, while the nitrogen substituent is a quaternary ammonium salt in the most potent anticholinergics. The carbon chain connecting the ester with the amine group can vary from two to four carbons, with the most potent agents having two methylene units. Agents with a tertiary amine also possess considerable antagonist activity. Anticholinergics compete with agonists for a common receptor. The presence of cyclic rings and aromatic groups enhances the binding of the antagonist to the receptor. As the antagonists are larger than agonists, their ring substitutions bind outside the acetylcholine binding site. This effectively blocks the agonist binding.