[4-[[N-(3-Chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium (McN-A-343)-related compounds. Effect of the butynyl chain inclusion into an aromatic unit on the potency for muscarinic receptors Original Research Article

A series of derivatives of the known M1 selective muscarinic receptor agonist McN-A-343 () was designed with the aim of investigating the effects of structural variations on both the butynyl chain and the phenyl ring of . The butynyl chain was replaced with an aromatic spacer, and the effects of such a modification on the stereoelectronic properties of the molecules were theoretically studied and considered compatible with muscarinic receptor affinity. Substituents on the phenyl ring of were selected so as to vary their electronic and hydrophobic properties. This design strategy did not produce muscarinic M1 receptor agonists more potent than the prototype , even if some analogues displayed functional selectivity for different muscarinic receptor subtypes. Compounds were selective agonists towards muscarinic M3 receptors, while compounds were selective muscarinic M2 receptor agonists. The most interesting derivative was , a full agonist at muscarinic M3 receptors devoid of activity at both muscarinic M1 and M2 subtypes. The pharmacological profile of the series was further characterized by studying the anticholinesterase and miotic activities of some representative compounds. Compounds turned out to be weak acetylcholinesterase inhibitors, while derivatives were able to significantly reduce the pupillary diameter in rabbit, indicating as an effective miotic agent.