Several thiophene N-substituted tetrahydropyridinyl compounds were synthesized and found to inhibit the specific binding of the antagonist [3H]N-methylscopolamine in radioligand muscarinic assays. All compounds were found to be selective partial agonists. Compound 7A in particular was found to be an absolute M2 selective partial agonist in functional assays. This compound stimulated GTPγS binding that reached about 76% EMAX of the full agonist carbachol and only activated M2 receptors. Other compounds were found to be potent and efficacious M2 partial agonists. Compound 7A and other analogs contain the NCCSC backbone which serves as a novel scaffold for the design and synthesis of agonists with absolute muscarinic functional selectivity.

Thiophene N-substituted tetrahydro pyridinium salts as functionally selective muscarinic partial agonists

249th National Meeting (2015)

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