EX-VIVO STUDIES WITH ILOPERIDONE (HP-873), A POTENTIAL ATYPICAL ANTIPSYCHOTIC WITH DOPAMINE D-2 5-HYDROXYTRYPTAMINE(2) RECEPTOR ANTAGONIST ACTIVITY/

Iloperidone {HP 873: l)1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone } is a dopamine (D-2)/serotonin (5-HT2) receptor antagonist with the p reclinical profile of an atypical antipsychotic based on biochemical s tudies in rats. Iloperidone significantly increased dopa accumulation, an index of dopamine turnover in response to D-2 receptor blockade, a t doses from 0.3 to 10 mg/kg i.p. in the striatum and from 1 to 10 mg/ kg in the nucleus accumbens. Blockade of dopaminergic presynaptic auto receptors was measured by the reversal of apomorphine-inhibition of ga mma-butyrolactone-induced dopa synthesis. Iloperidone did not signific antly reverse the apomorphine inhibition of gamma-butyrolactone-induce d dopa synthesis at any of the doses tested (0.3-10 mg/kg i.p.). In ex vivo receptor autoradiography studies, a 30-min pretreatment with ilo peridone (2.5-20 mg/kg i.p.) inhibited the binding of [H-3]spiperone t o cortical and subcortical 5-HT2 receptors by 42 to 94%, in contrast t o only 1 to 15% inhibition of [H-3]spiperone binding to D-2 receptors in the nucleus accumbens and striatum. Iloperidone, al 2.5 mg/kg i.p., inhibited 5-H-2 receptor binding by 54 to 62% at 4-hr post-treatment, whereas there was negligible inhibition of D-2 receptors. Chronic tre atment with 5 mg/kg i.p. of iloperidone for 19 days significantly decr eased the number of 5-HT2 receptors in the frontal cortex with no chan ge in receptor affinity. D-2 receptor number and affinity were unchang ed in the nucleus accumbens and six regions of the striatum. In summar y, iloperidone is a 5-HT and dopamine receptor antagonist with weak ac tivity at presynaptic dopamine autoreceptors. Potent 5-HT2 receptor an tagonism may be an important component in the preclinical profile of i loperidone as a potential atypical antipsychotic.