Abstract
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-HT3) 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-HT3 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.
