Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists |
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Authors: | Becker Daniel P Flynn Daniel L Moormann Alan E Nosal Roger Villamil Clara I Loeffler Richard Gullikson Gary W Moummi Chafiq Yang Dai-C |
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Affiliation: | Department of Medicinal Chemistry and Department of Pharmacology, Pfizer, 4901 Searle Parkway, Skokie, IL 60077, USA. dbecke3@luc.edu |
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Abstract: | A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT(4) and 5-HT(3) receptor binding, 5-HT(4) receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT(3) receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT(4) receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT(4) partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT(4) receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT(4) receptor antagonist with a pA(2) value of 8.13 in the rat TMM assay. N-Methyl indole ester 13d was identified as a potent 5-HT(4) antagonist with a pA(2) value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT(1), 5-HT(2), D(1), D(2), alpha(1), alpha(2), and beta receptors. |
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