3- [2- [4-(4-Fluorobenzoyl)piperidin- 1-yl]ethyl] -5,6,7,8-tetrahydro-4(3 H)-quinazolinones: serotonin 5-HT 2A receptor antagonists endowed with potent central action

Abstract

Summary A series of 5,6,7,8-tetrahydro-4(3 H )-quinazolinones substituted at the 3-position with 4-benzoyl-1-ethylpiperidine, 4-(4-fluorobenzoyl)-1-ethylpiperidine, 4-[bis-(4-fluorophenyl)methylene]-1-ethylpiperidine, or 4-(4-fluorophenyl)-1-propylpiperazine have been prepared and evaluated in binding assays to determine their affinity at serotonin 5-HT 2A receptors as well as in a functional test, ie, wet dog shakes (WDS) induced by L-5-hydroxytryptophan (L-5-HTP), a behavioural response which is mediated by stimulation of 5-HT 2A receptors. Among the compounds prepared, 3-[2-[4-(4-fluorobenzoyl)piperidin-l-yl]ethyl]-5,6,7,8-tetrahydro4 (3 H )-quinazolinone ( 10a ) and 2-methyl-3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-5,6,7,8-tetrahydro-4(3 H )-quinazolinone ( 10b ) proved to be the most potent 5-HT 2A receptor antagonists. In binding assays, the two compounds displayed similar affinity for 5-HT 2A receptors in the nanomolar range to ketanserin and ritanserin. In the WDS test, they were even more potent than ketanserin and ritanserin. Compound 10b , which was found to possess the highest potency and duration of action in the WDS test, was chosen for a preliminary evaluation of its ability to inhibit ethanol intake in rats, a response linked to blockade of the central 5-HT 2A receptors. This compound significantly reduced ethanol intake in rats from the first day of treatment. The results of the present study indicate that 10b is a potent centrally acting antagonist at 5-HT 2A receptors.