BIMT-17, A 5-HT2A RECEPTOR ANTAGONIST AND 5-HT1A RECEPTOR FULL AGONIST IN RAT CEREBRAL-CORTEX

In the search for antidepressant agents with a rapid onset of action, we have found that compound BIMT 17 (1-[2-[4-(3-trifluoromethy)phenyl) piperazin- 1-yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity f or cerebral cortical 5-HT1A (pK(i) = 7.72) and 5-HT2A (pK(i) = 6.90) r eceptors, with no appreciable affinity for the other 5-HT receptor sub types, including 5-HT2C. BIMT 17 reduced forskolin-stimulated cAMP acc umulation in the cerebral cortex (pEC(50) = 6.09) and in the hippocamp us (pEC(50) = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK(i) = 6.96) in the cerebral cortex. The effect on cAMP ac cumulation was blocked by the 5-HT1A receptor antagonist tertatolol. B uspirone, 8-OH-DPAT and S 14671 lamino)ethyl]-4[1-(7-methoxynaphtyl)]- piperazine}, claimed to be 5-HT1A receptor agonists, did not reduce fo rskolin-stimulated cAMP formation in the cerebral cortex. On the basis of these data, it was concluded that BIMT 17 was the only compound th at behaved as a full agonist with respect to the cAMP response in the cortex, while exerting concurrent agonism at 5-HT1A receptors and anta gonism at 5-HT2A receptors. These characteristics might explain the pe culiar behaviour of BIMT 17 in mimicking; the inhibitory action of 5-H T on the basal firing rate of the cortical neurons (see accompanying p aper).