So. Ogren et al., EFFECTS OF REMOXIPRIDES METABOLITES ON DOPAMINE-D2 RECEPTORS AND RECEPTOR FUNCTIONS IN THE RAT, Pharmacology & toxicology, 73(6), 1993, pp. 325-334
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.