Pharmacological studies in vivo with ICI 169,369, a chemically novel 5-HT2/5-HT1C receptor antagonist.
ICI 169,369 (2-(2-dimethylaminoethylthio-3-phenylquinoline hydrochloride) has been tested in vivo for its potency and selectivity as an antagonist at 5-HT2 and 5-HT1C receptors. It caused a 50% inhibition of 5-HTP-induced head twitches in mice and fenfluramine-induced hyperthermia in the rat at approximately 1 mg/kg following parenteral administration. Results showed that ICI 169,369 had good oral bioavailability, since in the fenfluramine test the oral and s.c. ID50 values were similar. ICI 169,369 was a selective antagonist of 5-HT-induced bronchoconstriction in the guinea-pig and 5-HT-induced pressor effects in the anaesthetised dog. In a series of other tests in vivo the compound was shown to be devoid of significant activity at alpha 1- and alpha 2-adrenoceptors, dopamine (D2), muscarinic (M1) and histamine (H1) receptors at 30-100 times its ID50 values used in the 5-HT tests. Thus, ICI 169,369 is a selective, orally active 5-HT2/5-HT1C antagonist that should prove useful in the analysis of the role of 5-HT in physiological and pathological states.
Blackburn
T P
TP
ICI Pharmaceuticals, Research Department II, Macclesfield, Cheshire, U.K.
Cox
B
B
Thornber
C W
CW
Pearce
R J
RJ
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003655:Decerebrate State; D004285:Dogs; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010095:Oxotremorine / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012472:Salivation / Q000187:drug effects; D012701:Serotonin; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects
D011804:Quinolines; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D005277:Fenfluramine; D012701:Serotonin; D010095:Oxotremorine; C054363:2-((2-(dimethylamino)ethyl)thio)-3-phenylquinoline; D000661:Amphetamine