EFFECTS OF REMOXIPRIDES METABOLITES ON DOPAMINE-D2 RECEPTORS AND RECEPTOR FUNCTIONS IN THE RAT

The main metabolites of remoxipride formed in rat and man were examine d for their affinities for the [H-3] SCH 23390-labelled DA D1 and [H-3 ]-raclopride-labelled D2 receptors in rat striatal homogenates. In add ition, their effectiveness in blocking postsynaptic DA receptor activi ty in vivo was measured by the use of several different test models in the male rat. Phenolic metabolites formed mainly in the rat retained (similar to remoxipride) their selectivity for the D2 receptor with ve ry low affinities for the D1 receptor. The pyrrolidone metabolites for med mainly in man showed very low affinities for both the D1 and D2 re ceptors. The ability of the metabolites to block postsynaptic DA recep tor activity in vivo correlated with their affinities for the D2 recep tor. Among the metabolites tested, the phenolic compounds FLA 797 (-) and FLA 908 (-) were much more effective than remoxipride in inducing catalepsy, which is consistent with a higher affinity for [H-3] raclop ride labelled striatal D2 receptors. However, analysis of the effectiv eness of the DA receptor blockade (blockade of d-amphetamine locomotio n or DA agonist hypothermia) after intraperitoneal or subcutaneous adm inistration suggested that FLA 797 (-)/FLA 908 (-) may only contribute marginally to the D2 receptor-blocking activity of remoxipride in the rat. This conclusion was further supported by the observation that th e atypical antipsychotic profile of remoxipride was not mimicked by th e active metabolites. The weak DA D2 blocking effect of the pyrrolidon e metabolites indicated that remoxipride is responsible for the clinic al action.