Muscarinic acetylcholine receptors, belonging to the G protein-coupled receptor (GPCR) family, are known to play important biological roles due to their extensive distribution in various tissue types. Due to highly conserved orthosteric sites amongst the receptor family, the design and synthesis of selective and efficacious muscarinic receptor dualsteric ligands may provide a viable approach for the treatment of certain central nervous and peripheral system disorders. Derivatives of 4-hexyloxy-1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium and 4-hexyloxy-(4-oxidobenzoyloxy)-3-quinuclidinyl-1-ium were found to non-competitively antagonize functional response to carbachol with high potencies in the nanomolar range. Under washing condition, the half-life of antagonistic actions was found to be several hours. Overall, compounds were determined to be potent long-acting antagonists. These novel prototypical functionally selective antagonists may be of therapeutic interest for the treatment of several disease states.

Synthesis of novel functionally selective and long-acting muscarinic antagonists

2019 Spring National Meeting

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