title: Characterization of YM060, a potent and selective 5-hydroxytryptamine3 receptor antagonist, in rabbit nodose ganglion and N1E-115 neuroblastoma cells.
abstract: The 5-hydroxytryptamine (5-HT)3 receptor blocking properties of YM060, [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride], were examined by electrophysiological and radioligand binding studies. Results were compared with those for ondansetron, granisetron and the enantiomer (S-form) of YM060. 5-HT and 2-methyl-5-HT, a selective 5-HT3 receptor agonist, induced dose-dependent depolarizations of rabbit nodose ganglion with ED50 values of 24.0 (19.9-29.1) and 40.1 (30.9-52.1) nmol, respectively (geometric mean, 95% CL). YM060, ondansetron, granisetron and the S-form dose-dependently inhibited 5-HT-induced depolarizations with IC50 values of 3.85 (2.47-5.98), 1.55 (1.26-1.91), 1.45 (1.18-1.79) and 13.5 (11.2-16.2) nM, respectively. Methysergide, a 5-HT1-like and 5-HT2 receptor antagonist, at a concentration of 10(-5) M had no effect on responses to 5-HT. YM060 up to 10(-5) M produced no significant depression of depolarizing responses to 1,1-dimethyl-4-phenylpiperazinium iodide and gamma-aminobutyric acid. YM060, ondansetron, granisetron and the S-form displaced specific binding of [3H]GR65630 to N1E-115 neuroblastoma cell membranes with Ki values of 0.091 (0.086-0.097), 7.03 (5.96-8.01), 2.02 (1.74-2.30) and 10.3 (9.96-10.6) nM, respectively. These results show that YM060, compared with ondansetron and granisetron, has considerably higher affinity for 5-HT3 receptors in N1E-115 cells and slightly less potent 5-HT3 receptor antagonistic activity in rabbit nodose ganglion. Moreover, the isomeric activity ratio (R-form/S-form) was approximately 112 in N1E-115 cells and no greater than 4 in the ganglion.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Medicinal Research Laboratories I, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
authors: H
authors: H
authors: Ito
authors: K
authors: K
authors: Hidaka
authors: K
authors: K
authors: Miyata
authors: T
authors: T
authors: Kamato
authors: A
authors: A
authors: Nishida
authors: K
authors: K
authors: Honda
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D008297:Male; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009620:Nodose Ganglion / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D007211:Indoles; D012702:Serotonin Antagonists; C059068:GR 65630; D012701:Serotonin; C045918:2-methyl-5-HT; C071315:ramosetron