- Pyrrolizidine esters and amides as 5-HT4 receptor agonists and antagonists
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A series of pyrrolizidine esters, amides, and ureas was prepared and tested for 5-HT4 and 5-HT3 receptor binding, 5-HT4 receptor agonism in the rat tunica muscularis mucosae (TMM) assay, and for 5-HT3 receptor-mediated functional antagonism in the Bezold-Jarisch reflex assay. Several pyrrolizidine derivatives were identified with high affinity for the 5-HT4 receptor, including benzamide 12a (SC-53116), a potent and selective 5-HT4 partial agonist that exhibits efficacy in promoting antral contractions and activity in promoting gastric emptying in canine models. Also discovered were 5-HT4 receptor antagonists, including imidazopyridine amide 12h (SC-53606), which is a potent and selective 5-HT4 receptor antagonist with a pA2 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 pA2 value of 8.93. High selectivity was observed for these pyrrolizidine derivatives versus other monoamine receptors, including 5-HT1, 5-HT2, D1, D 2, α1, α2, and β receptors. 2006 American Chemical Society.
- 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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p. 1125 - 1139
(2007/10/03)
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- Self-condensation of N-tert-butanesulfinyl aldimines: Application to the rapid asymmetric synthesis of biologically important amine-containing compounds
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(Chemical Equation Presented) Highly diastereoselective intra- and intermolecular self-condensation reactions of N-tert-butanesulfinyl aldimines have been developed and applied to the rapid, asymmetric synthesis of frans-2-aminocyclopentanecarboxylic acid and the drug candidate SC-53116. Key to both syntheses is a novel microwave-assisted reaction in which N-sulfinyl aldimines are cleanly converted into nitrites in high-yielding concerted elimination processes.
- Schenkel, Laurie B.,Ellman, Jonathan A.
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p. 3621 - 3624
(2007/10/03)
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