BIMT 17, a 5-HT sub(2A) receptor antagonist and 5-HT sub(1A) 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-trifluoromethylphenyl)piperazin-1-yl] ethyl]benzimidazol-[1H]-2-on shows a good affinity for cerebral cortical 5-HT sub(IA) (pK sub(i) = 7.72) and 5-HT sub(2A) (pK sub(i) = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT sub(2C). BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC sub(50) = 6.09) and in the hippocampus (pEC sub(50) = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pK sub(i) = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT sub(1A) receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 {1-[2(2-thenoylamino)ethyl]-4[1-(7-methoxy naphtyl)]-piperazine} , claimed to be 5-HT sub(1A) receptor agonists, did not reduce forskolin-stimulated cAMP formation in the cerebral cortex. On the basis of these data, it was concluded that BIMT 17 was the only compound that behaved as a full agonist with respect to the cAMP response in the cortex, while exerting concurrent agonism at 5-HT sub(1A) receptors and antagonism at 5-HT sub(2A) receptors. These characteristics might explain the peculiar behavior of BIMT 17 in mimicking the inhibitory action of 5-HT on the basal firing rate of the cortical neurons.