Robert James Pearce

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.