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.