Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain.
The novel substituted benzamide, remoxipride, preferentially blocked apomorphine-induced hyperactivity with weak effects on stereotypies. The potency of remoxipride was about 50 times higher than that of sulpiride. Remoxipride caused a weak, atypical form of catalepsy and showed a high separation between the ED50 for blockade of apomorphine-induced hyperactivity and the ED50 for induction of catalepsy (ratio 24). Remoxipride was shown to be a selective dopamine D2 receptor antagonist since it displaced [3H]spiperone (IC50 = 1570 nM) but not [3H]flupentixol (IC50 greater than 100 000 nM) in rat striatum, and did not inhibit striatal DA-sensitive adenylate cyclase in vitro (IC50 greater than 100 000 nM). Remoxipride is a potent antagonist of D2 receptors showing a dose-dependent blockade of [3H]spiperone and [3H]n-propylnorapomorphine in vivo binding with a potency equal to that of chlorpromazine. In contrast to haloperidol, remoxipride caused a preferential blockade of in vivo [3H]spierone binding in the mesolimbic DA rich areas and the substantia nigra with much less effect in the striatum. In addition, remoxipride produced a preferential increase of DA utilization following synthesis inhibition in the olfactory tubercle. Only minor changes in NA and 5-HT metabolism were observed while HVA and DOPAC levels were markedly elevated. Taken together, these results indicate that remoxipride is a potent, selective D2 receptor blocking agent with a preferential action in mesolimbic and extrastriatal dopamine-containing neurons.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001667:Binding, Competitive; D001923:Brain Chemistry / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D002746:Chlorpromazine / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006651:Histocytochemistry; D006801:Humans; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017330:Remoxipride; D013134:Spiperone; D013469:Sulpiride / Q000494:pharmacology; D013881:Thioridazine / Q000494:pharmacology; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D014150:Antipsychotic Agents; D001549:Benzamides; D011954:Receptors, Dopamine; D017330:Remoxipride; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D013469:Sulpiride; D000262:Adenylyl Cyclases; D006220:Haloperidol; D001058:Apomorphine; D013881:Thioridazine; D002746:Chlorpromazine