title: The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat.
abstract: The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.
authors.affiliation: GlaxoWellcome, Stevenage, Herts., UK. nc0537@ggr.co.uk
authors.forename: N M
authors.initials: NM
authors.lastname: Clayton
authors.forename: R
authors.initials: R
authors.lastname: Sargent
authors.forename: A
authors.initials: A
authors.lastname: Butler
authors.forename: J
authors.initials: J
authors.lastname: Gale
authors.forename: M P
authors.initials: MP
authors.lastname: Maxwell
authors.forename: A A
authors.initials: AA
authors.lastname: Hunt
authors.forename: V J
authors.initials: VJ
authors.lastname: Barrett
authors.forename: D
authors.initials: D
authors.lastname: Cambridge
authors.forename: C
authors.initials: C
authors.lastname: Bountra
authors.forename: P P
authors.initials: PP
authors.lastname: Humphrey
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002243:Carbolines / Q000627:therapeutic use*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005215:Fasting; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects*; D017294:Ondansetron / Q000494:pharmacology; D010047:Ovalbumin / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D012016:Reference Values; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D014630:Vagus Nerve / Q000187:drug effects
chemical_list: D000316:Adrenergic alpha-Agonists; D002243:Carbolines; D012702:Serotonin Antagonists; C090840:alosetron; D017294:Ondansetron; C016986:apraclonidine; D010047:Ovalbumin; D003000:Clonidine