Piperazine derivatives including the putative anxiolytic drugs,buspirone and ipsapirone,are agonists at 5-HT1A receptors negatively coupled with adenylate cyclase in hippocampal neurons

Summary Two putative anxiolytic drugs [ipsapirone (TVXQ 7821) and buspirone], structurally unrelated to benzodiazepines, have negligible ataxic and sedative side effects. These drugs are piperazine analogs which interact at 5-HT₁ binding sites. It is demonstrated here that these drugs and two other piperazine derivatives, trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (mCPP), are agonists at 5-HT_1A receptors, a subclass of the 5-HT₁ receptor, mediating inhibition of forskolin (100 M) stimulated adenylate cyclase in particulate fractions of guinea pig hippocampus as well as inhibition of the formation of cyclic AMP promoted by vasoactive intestinal polypeptide (0.1 M) plus forskolin (1 M) in mouse hippocampal neurons in primary culture. This study demonstrates that these piperazine based drugs act in both brain homogenate preparations and in intact neurons in a similar manner. The biochemical models described here may aid in the development of even more active drugs in this class.This work was supported by grants from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Direction des Recherches Etudes et Techniques (DRET, N°85/188) of the French Defense Ministry and by the Direction and Ministère de la Recherche ScientifiqueSend offprint requests to J. Bockaert at the above address