Behavioural studies on WAY100289, a novel 5-HT3 receptor antagonist, in two animal models of anxiety.
The novel 5-HT3 receptor antagonist, WAY100289, was examined in two animal models of anxiety: the mouse two-compartment light: dark box, and the rat potentiated acoustic startle paradigm. The activity of WAY100289 in the light: dark box model was also compared with that of the selective 5-HT3 receptor antagonists ondansetron, zacopride, ICS-205,930 and quaternary ICS-205,930 (QICS). WAY100289 mimicked the activity profile of benzodiazepine positive controls in the mouse light: dark box, i.e. WAY100289 markedly and significantly increased the exploratory activity of mice in the more aversive light compartment, at doses of 0.01-1.0 mg/kg s.c. and 0.1-10.0 mg/kg p.o. Zacopride and ondansetron induced comparable effects at doses of 0.001-1.0 mg/kg s.c. ICS-205,930 displayed a markedly biphasic dose-response relationship; being active at 0.01 mg/kg s.c., but not at higher or lower doses. QICS was not active in the light: dark box up to a dose of 10 mg/kg s.c., suggesting that the compound does not enter the brain readily. WAY100289 was also active in the rat potentiated acoustic startle model, significantly attenuating the potentiated startle response at doses of 0.03 and 0.3 mg/kg s.c. The activity profile of WAY100289 in this model resembled that of ondansetron. These data strongly suggest that WAY100289 may possess anxiolytic properties in the clinic.
Bill
D J
DJ
Department of Biomedical Research, Wyeth Research Ltd., Maidenhead, Berkshire, UK.
Fletcher
A
A
Glenn
B D
BD
Knight
M
M
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D011897:Random Allocation; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects*; D012702:Serotonin Antagonists
D014151:Anti-Anxiety Agents; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C077614:WAY 100289