title: Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. III. Pharmacological evaluations and molecular modeling studies of optically active 4,5,6,7-tetrahydro-1H-benzimidazole derivatives.
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-hydroxytrptamine (5-HT3) receptor antagonist, as judged from they 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 (ramosetron = 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 restricted 4,5,6,7-tetrahydro-1H-benzimidazole ring in "equatorial-twist" conformation. In our pharmacophore model for the 5-HT3 receptor antagonist, a basic center exists 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.
authors.affiliation: Neuroscience/Gastrointestinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd. Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Furuya
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Tokunaga
authors.forename: K
authors.initials: K
authors.lastname: Miyata
authors.forename: I
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D002945:Cisplatin; D018360:Crystallography, X-Ray; D003672:Defecation / Q000187:drug effects; D005289:Ferrets; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D017294:Ondansetron / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
chemical_list: D001562:Benzimidazoles; D012702:Serotonin Antagonists; C085986:YM 114; D017294:Ondansetron; C071315:ramosetron; D002945:Cisplatin