Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. Novel long acting muscarinic antagonists were synthesized and tested for biological activity in CHO cells expressing individual subtypes of muscarinic receptors. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. The 4-hexyloxy-1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium derivatives were found to non-competitively antagonized functional response to carbachol with potencies ranging from 20 nM ( pKB 7.68, α 0.0011) at M1 to 3 µM at M3 receptors. Under washing condition, half-life of antagonistic action ranged from 1.7 at M2 to 5 hours at M5 receptors. Overall, these derivatives were found to be potent long-acting M1-preferred antagonists. M1-preferred muscarinic antagonists are therapeutic targets for a number of neurological and psychiatric disease states. word

Synthesis and biological evaluation of novel long acting muscarinic antagonists

255th National Meeting (2018)

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