Substituted benzamides as cerebral dopamine antagonists in rodents

The substituted benzamides metoclopramide, sulpiride, tigan and clebopride and its debenzylated metabolite (DP) were compared for their ability to act as dopamine antagonists in rodents. All compounds inhibited apomorphine-induced circling in animals with unilateral nigro-striatal lesions; all except tigan inhibited the apomorphine-induced reversal of reserpine akinesia; and all induced some degree of catalepsy. The potency of the compounds in these behavioural experiments ranked in the order : clebopride > metoclopramide > sulpiride > tigan and DP. Striatal and mesolimbic HVA levels were elevated to a variable degree by all compounds. Their potency in elevating striatal HVA ranked in the order : clebopride > metoclopramide > sulpiride > tigan and DP. The benzamides, in general, elevated both striatal and mesolimbic HVA to the same degree. Metoclopramide and clebopride produced an increase in striatal and mesolimbic DOPAC only at high dosage levels; sulpiride, however, elevated the levels of both dopamine metabolites concommittantly. This data suggests that such substituted benzamides produce a functional blockade of cerebral dopamine receptors. However, metoclopramide, sulpiride, tigan and DP were without effect on the in vitro dopamine sensitive adenylate cyclase system from rat striatum. Clebopride in high concentrations caused a small reduction in dopamine stimulation of cyclic AMP production. All compounds induced ipsilateral circling in apomorphine-treated rats when injected directly into one striatum, which makes the possibility that their actions are due to active metabolites unlikely. This data suggests that substituted benzamides form a pharmacologically-distinct group of dopamine antagonists, whose mechanism of action differs from that of classical neuroleptics. Also, there may be differences in the modes of action of various benzamides, to explain their varying clinical potencies.