Novel 5-Hydroxytryptamine (5-HT_3) Receptor Antagonists. III. Pharmacological Evaluations and Molecular Modeling Studies of Optically Active 4,5,6,7-Tetrahydro-1H-benzimidazole Derivatives

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The R- and S-enantiomers of the 4,5,6,7-tetrahydro-1H-benzimidazole derivatives 3-8 were prepared by optical resolution. Each R-isomer, except for 3,was almost two orders of magnitude more potent than its S-isomer as a 5-hydroxytryptamine (5-HT_3) receptor antagonist, as judged from the effect on the von Bezold-Jarisch reflex (B. J. reflex) in rats, the contraction of isolated guinea-pig colon and the receptor-binding affinity. The (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] derivative 6R・HCl (remosetron=YM060) and (-)-(R)-5-[(1-indolinyl)carbonyl] derivative 4R・HCl (YM114=KAE-393) given p.o. were hundreds of times more potent than 1 (ondansetron) and 2 (granisetron) in their inhibitory effects on cisplatin-induced emesis in ferrets and restraint stress-induced increases in fecal pellet output in rats. Three-dimensional molecular modeling studies suggested that the 'chiral selection' of the enantiomers might be influenced by the steric repulsion between the aromatic ring part and the conformationally resricted 4,5,6,7-tetrhydro-1H-benzimidazole ring in "equatorial-twist" conformation. In our pharmacophore model for the 5-HT_3 receptor antagonist, a basic center exsts at the left side of the aromatic-carbonyl plane when viewing from the aromatic part with the carbonyl oxygen atom upwards, whereas the "handedness" is ambiguous in the previously proposed model.
公益社団法人日本薬学会の論文
1996-09-15