3-[[(ARYLOXY)ALKYL]PIPERIDINYL]-1,2-BENZISOXAZOLES AS D-2 5-HT2 ANTAGONISTS WITH POTENTIAL ATYPICAL ANTIPSYCHOTIC ACTIVITY - ANTIPSYCHOTIC PROFILE OF ILOPERIDONE (HP-873)/

A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was syn thesized and evaluated as potential antipsychotic D-2/5-HT2 antagonist s. Most of these compounds showed potent antipsychotic-like activity i n an apomorphine-induced climbing mouse paradigm, with many also showi ng preferential mesolimbic activity, as indicated by their weaker effe cts in an apomorphine-induced stereotypy model. In receptor binding as says, many displayed a moderate affinity for the D-2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor. a proper ty that has been suggested as necessary for atypicality. From this ser ies, compound 45, l)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone ( iloperidone, HP 873), was further evaluated in a battery of in vivo an d in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction o f catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it sh owed positive activity in a social interaction paradigm, suggesting po tential efficacy;against asociality, a component of the negative sympt oms of schizophrenia. In chronic ex vivo studies, 45, similar to cloza pine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D-2 receptors. Compound 45 is currently undergoing clin ical evaluation.