Document Type

Article

Publication Date

2-9-2006

Publication Title

Journal of Medicinal Chemistry

Volume

49

Issue

3

Publisher Name

American Chemical Society

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.

Comments

Author Posting © American Chemical Society, 2006. This is the author's version of the work. It is posted here by permission of American Chemical Society for personal use, not for redistribution. The definitive version was published in Journal of Medicinal Chemistry, Volume 49, Issue 3, February 9, 2006. http://dx.doi.org/10.1021/jm0509501

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Creative Commons License
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