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-trifluoromethylphenyl)piperazin-1- yl]ethyl]benzimidazol-[1H]-2-one) shows a good affinity for cerebral cortical 5-HT1A (pKi = 7.72) and 5-HT2A (pKi = 6.90) receptors, with no appreciable affinity for the other 5-HT receptor subtypes, including 5-HT2C. BIMT 17 reduced forskolin-stimulated cAMP accumulation in the cerebral cortex (pEC50 = 6.09) and in the hippocampus (pEC50 = 6.50), and antagonized 5-HT-induced phosphatidylinositol turnover (pKi = 6.96) in the cerebral cortex. The effect on cAMP accumulation was blocked by the 5-HT1A receptor antagonist tertatolol. Buspirone, 8-OH-DPAT and S 14671 (1-[2-(2-thenoylamino)ethyl]- 4[1-(7-methoxynaphtyl)]-piperazine), claimed to be 5-HT1A 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-HT1A receptors and antagonism at 5-HT2A 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 (see accompanying paper).
Borsini
F
F
Research Division, Boehringer Ingelheim Italia, Milano, Italy.
Giraldo
E
E
Monferini
E
E
Antonini
G
G
Parenti
M
M
Bietti
G
G
Donetti
A
A
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D015290:Second Messenger Systems; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*
D000928:Antidepressive Agents; D001562:Benzimidazoles; D010716:Phosphatidylinositols; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C098107:flibanserin; D000242:Cyclic AMP