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Cholinergic Antagonists: Chemistry and Structure-Activity Relationship

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Cholinergic antagonists, or parasympatholytics, block ACh activity at both muscarinic and nicotinic receptors.

Agents that selectively block muscarinic receptors are called antimuscarinics.

The antimuscarinics include naturally occurring alkaloids; their semisynthetic derivatives—which differ in their distribution and duration of action from the parent compound; and synthetic compounds—which are selective to specific receptor subtypes.

Atropine—the prototype antimuscarinic—is an ester of tropic acid and tropine. Its structure resembles acetylcholine and is used as a reference for designing many antimuscarinic agents.

In general, most antimuscarinics contain an ester and a basic amine group separated by a two-to-four carbon linker.

Compounds having aromatic, cyclic, or –OH substitutions in the acyl portion of the ester enhance the antimuscarinic effect.

Further, quaternary ammonium derivatives are comparatively more potent than parent compounds.

In nature, atropine exists as an l(^_) isomer which is 100-fold more potent than a d(+) isomer. As it racemizes rapidly, the racemic mixture of atropine is used therapeutically.

Overview

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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.

Transcript

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Cholinergic Antagonists

Muscarinic Antagonists

Nicotinic Antagonists

Structure Activity Relationship

Anticholinergic Chemistry

Ester Group Analysis

Nitrogen Substituent Effects

Carbon Linker Variants

Receptor Binding Affinity

Cyclic Ring Enhancement