Effects of remoxipride's metabolites on dopamine D2 receptors and receptor functions in the rat.

ABSTRACT

The main metabolites of remoxipride formed in rat and man were examined for their affinities for the [3H] SCH 23390-labelled DA D1 and [3H]-raclopride-labelled D2 receptors in rat striatal homogenates. In addition, their effectiveness in blocking postsynaptic DA receptor activity 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 very low affinities for the D1 receptor. The pyrrolidone metabolites formed mainly in man showed very low affinities for both the D1 and D2 receptors. The ability of the metabolites to block postsynaptic DA receptor activity in vivo correlated with their affinities for the D2 receptor. 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 [3H] raclopride labelled striatal D2 receptors. However, analysis of the effectiveness of the DA receptor blockade (blockade of d-amphetamine locomotion or DA agonist hypothermia) after intraperitoneal or subcutaneous administration 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 the atypical antipsychotic profile of remoxipride was not mimicked by the active metabolites. The weak DA D2 blocking effect of the pyrrolidone metabolites indicated that remoxipride is responsible for the clinical action.