Buspirone is the first of several N‐alkyl‐substituted aryl‐piperazine‐containing drugs to be approved for use as an anxiolytic agent. These drugs do not interact with the benzodiazepine‐GABA receptor complex and therefore do not share the sedating and anticonvulsant effects of benzodiazepines. Buspirone and its analogs, gepirone and ipsapirone, act as agonists both pre‐ and postsynaptically at 5HTla receptor sites. A series of piperazine‐containing drugs was tested for their affinity at the 5HTla (postsynaptic) binding sites in hippocampus and compared with their ability to inhibit isolation‐induced aggression by mice. The potent 5HTla agonist, 8‐OH‐DPAT, was the most potent drug in both tests: IC50 = 1 nM, and ED50 = 2.4 μmol/kg for inhibition of (3H)‐5HT binding and aggression, respectively. There was a good correlation between ability to inhibit aggression and ability to inhibit (3H)‐5HT binding to hippocampal membranes. Fluprazine (DU 27716) was the major exception, but results with SKF 525‐A pretreatment to inhibit drug oxidation suggest that both fluprazine and metabolites have antiaggressive activity. Like other aryl‐piperazine drugs, fluprazine is potentiated by coadministration of a postsynaptic 5HT receptor antagonist, methysergide. Since antagonists of postsynaptic 5HT receptors potentiate gepirone and 8‐OH‐DPAT inhibition of aggression, these data suggest that affinity for 5HTla receptors at presynaptic autoreceptor sites is critical for the antiaggressive activity of these drugs and possibly for their anxiolytic effects.
Drug Development Research – Wiley
Published: Jan 1, 1988
Keywords: anxiolytics; buspirone; ipsapirone; 8‐OH‐DPAT
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