4-(6-FLUOROBENZISOXAZOL-3-YL)PIPERIDINE, A RISPERIDONE METABOLITE WITH SEROTONERGIC ACTIVITY OF POTENTIAL CLINICAL-SIGNIFICANCE

Because 6-FBIP [4-(6-fluorobenzisoxazol-3-yl)piperidine] has been iden tified as a metabolite of the antipsychotic agent risperidone, and due to its structural resemblance to certain serotonin agonists, it was o f interest to determine whether or not this metabolite possesses any 5 -HT2 activity of its own. In comparing the binding of this agent with that of its non-metabolite positional isomer control, 5-FBIP, it was f ound that 6-FBIP (5-HT2A Ki = 49 nM) binds with only 16-fold lower aff inity than risperidone, whereas the affinity of 5-FBIP is approximatel y 1000-fold lower. In tests of functional activity (inositol phosphate production, stimulus generalization in DOM-trained rats), however, 6- FBIP behaved as a 5-HT2 antagonist. It is concluded that 6-FBIP, altho ugh weaker than risperidone, would likely act as a 5-HT2 antagonist if it was produced to any significant extent upon metabolism of risperid one.