Synthesis and muscarinic M(2) subtype antagonistic activity of enantiomeric pairs of 3-demethylhimbacine (3-norhimbacine) and its C(4)-epimer |
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Authors: | Takadoi Masanori Yamaguchi Kentaro Terashima Shiro |
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Affiliation: | Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1Nogi, Nogi-machi, Tochigi, Japan. masanori.takadoi@mb2.kyorin-pharm.co.jp |
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Abstract: | In the course of our studies of the structure-activity relationships of himbacine 1, a potent antagonist of the M(2) subtype of muscarinic receptor, the four title compounds, 2, ent-2, 3, and ent-3, were synthesized with a highly stereoselective intermolecular Diels-Alder reaction of tetrahydroisobenzofuran 4 with achiral furan-2(5H)-one 5 as a key step, followed by simultaneous optical resolution and epimer separation of the racemic intermediates. Among these compounds, 3-demethylhimbacine (3-norhimbacine) 2, bearing an absolute configuration corresponding to that of 1, was found to show more potent muscarinic M(2) subtype receptor binding activity than natural 1. |
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