Nomifensine: a potent dopaminergic agonist of antiparkinson potential

Abstract

Nomifensine was shown to be a potent stereotypic agent in rat. Its effect was resistant to a-methylparatyrosine pretreatment but was abolished by combined reserpine/alpha-methylparatyrosine and by haloperidol. Electrolytic lesions placed in dopamine-containing areas of the extra-pyramidal, mesolimbic and amygdaloid systems indicated an effect in all areas, but the globus pallidus and substantianigra were shown to be most important for its action. Also the effect of nomifensine was reduced by lesions of the medial and/or dorsal raphé nuclei. A circling behaviour was recorded following nomifensine administration to animals with unilateral electrolytic lesions of the substantia nigra or asymmetric lesions of the medial raphé nucleus. These effects were resistant to alpha-methylparatyrosine and inhibited by haloperidol. Nomifensine reduced the intensity of harmine-induced tremor. The M2-metabolic of nomifensine mimicked the effects of the parent compound on peripheral administration bu the onset of action was more rapid and the duration shorter. The M2-metabolite was active on intrastriatal injection to induce stereotyped/hyperactive behaviour and contralateral asymmetries. In all experimental situations nomifensine was compared with apomorphine and d-amphetamine (dopamine and L-Dopa where appropriate). Nomifensine/metabolite was shown to be a potent dopaminergic agonist with an action mainly dependent upon functioning of the extrapyramidal system and partly independent of presynaptic mechanisms.