THIOPHENE N-SUBSTITUTED TETRAHYDRO PYRIDINIUM SALTS AS M₂ FUNCTIONALLY SELECTIVE MUSCARINIC PARTIAL AGONISTS

Qiwen Su

John Boulos

Barry university

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 in Chinese hamster ovary cell lines with comparable level of receptor density. All compounds were found to be selective partial agonists. Compounds 6A, 6C, 7A and 7C in particular were found to be M₂ selective partial agonists in functional assays. These compounds stimulated GTPγS binding ranging from 15% (6A) to 76% (7A) E_MAX 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.