title: BRL 46470 potently antagonizes neural responses activated by 5-HT3 receptors.
abstract: The effect of a novel 5-HT3 receptor antagonist, BRL 46470, has been studied on two electrophysiological models for 5-HT3 receptors: grease-gap recordings from rat isolated vagus nerve and whole-cell patch-clamp recordings from mouse neuroblastoma-rat glioma NG108-15 cells. Its action on the rat vagus nerve was compared to that of four other 5-HT3 receptor antagonists. On the rat vagus, BRL 46470 reduced the maximum depolarizing response to 5-HT in a concentration-dependent manner with an IC50 of 0.3-1.0 nM, but the EC50 for 5-HT was not appreciably affected. This action was similar to that of granisetron and ICS 205-930, but differed from that of GR38032F and (+)-tubocurarine which produced clear rightward shifts of the concentration-response curve to 5-HT. The 5-HT-induced fast inward current of voltage-clamped NG108-15 cells was also antagonized by 1 nM BRL 46470 in an insurmountable manner. In contrast to (+)-tubocurarine, the action of BRL 46470 on the rat vagus nerve and NG108-15 cells did not readily reverse on washing with antagonist-free medium. It is concluded that BRL 46470 is a potent, insurmountable 5-HT3 receptor antagonist on the rat vagus and NG108-15 cells.
authors.affiliation: Oxford University-SmithKline Beecham Centre for Applied Neuropsychobiology, University Department of Clinical Pharmacology, U.K.
authors.forename: N R
authors.initials: NR
authors.lastname: Newberry
authors.forename: C J
authors.initials: CJ
authors.lastname: Watkins
authors.forename: T S
authors.initials: TS
authors.lastname: Sprosen
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
authors.forename: D G
authors.initials: DG
authors.lastname: Grahame-Smith
authors.forename: R A
authors.initials: RA
authors.lastname: Leslie
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004594:Electrophysiology; D005910:Glioma / Q000503:physiopathology; D017829:Granisetron / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D009447:Neuroblastoma / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D017294:Ondansetron / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000494:pharmacology; D000077526:Tropisetron; D014403:Tubocurarine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014630:Vagus Nerve / Q000187:drug effects
chemical_list: D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017829:Granisetron; D007211:Indoles; D017294:Ondansetron; D012702:Serotonin Antagonists; D000077526:Tropisetron; D014403:Tubocurarine; C075685:BRL 46470