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

Article abstract of DOI:10.1016/S0223-5234(97)83291-6

A series of 5,6,7,8-tetrahydro-4(3H)-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-1-yl]ethyl]-5,6,7,8-tetrahydro-4(3H) -quinazolinone (10a) and 2-methyl-3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-5,6,7,8-tetrahydro -4(3H)-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.