Remoxipride shows low propensity to block functional striatal dopamine D2 receptors in vitro

Abstract The effect of remoxipride ((S)(−)-3-bromo- N -[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide) on dopamine D 2 receptor-mediated inhibition of cAMP formation in rat striatal tissue pieces was established together with that of a number of other dopamine D 2 receptor antagonists. The action of remoxipride, three other substituted benzamides, (−)-sulpiride, raclopride and NCQ 298 ((S)-3-iodo- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide mesylate) and haloperidol, a butyrophenone, was studied in the presence of (I) (+-) SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (100 μM) plus pergolide (1 μM) or (II) forskolin (1 μM) plus dopamine (100 μM). In addition, four of the metabolites of remoxipride: FLA 797 ((S)-3-bromo-N[1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6-methoxybenzamide), NCR 181 ((S)(−)-5-bromo- N -[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6-methoxybenzamide tartrate), NCQ 436 ((S)(−)- 3-bromo- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dihydroxy-2-methoxybenzamide semioxalate) and NCQ 469 ((S)(−)-3-bromo- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5-hydroxy-2,6-dimethoxybenzamide hydrochloride), mainly found in rodents, were studied using test system I. The results demonstrate that remoxipride is significantly weaker in blocking functional striatal dopamine D 2 receptors than either of the reference compounds studied and three of the four metabolites. The studies also demonstrate that dopamine D 1 and D 2 receptor interactions at the level of cAMP formation in the striatum are independent of action potentials or Ca 2+ .