The effect of the 5-HT3 receptor antagonist, RS-42358-197, in animal models of anxiety.
The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H- benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.
Costall
B
B
Postgraduate Studies in Pharmacology, School of Pharmacology, University of Bradford, West Yorkshire, UK.
Domeney
A M
AM
Kelly
M E
ME
Tomkins
D M
DM
Naylor
R J
RJ
Wong
E H
EH
Smith
W L
WL
Whiting
R L
RL
Eglen
R M
RM
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002144:Callithrix; D004195:Disease Models, Animal; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012702:Serotonin Antagonists / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines
D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D012702:Serotonin Antagonists; D044005:Tetrahydroisoquinolines; C079791:RS 42358-197