Pharmacological and biochemical studies with three metabolites of nomifensine

Abstract

Three major metabolites (M₁, M₂, M₃) of nomifensine (8-amino-1,2,3,4-tetrahydro-2-methyl-4-phenyl-isoquinoline) are formed by hydroxylation and methoxylation of the phenyl ring. They were compared with nomifensine

• 1. in various psychopharmacological tests in vivo, carried out in mice after oral or i.p. treatment and

• 2. in neurochemical in vitro studies, measuring inhibition of noradrenaline (NA), dopamine (DA), and serotonin (5-HT) uptake in rat brain synaptosomes.

M₁ (4′-hydroxy-nomifensine) was the most active metabolite, while M₂ and M₃ had little or no effect in pharmacological tests. M₁ reversed reserpine hypothermia in doses >2.5 mg/kg, antagonized tetrabenazine catalepsy (ED₅₀ 68 mg/kg) and reversed oxotremorine hypothermia (ED₅₀ 33 mg/kg). In these tests nomifensine was also active, being about 3–10 times more potent than M₁. In contrast to nomifensine M₁ had also serotoninergic activity, potentiating both phenelzine-induced twitching (ED₅₀ 11 mg/kg) and the anticonvulsant effect of 5-hydroxytryptophan. Moreover, M₁ prolonged the hexobarbital sleeping time in doses >10 mg/kg, prevented nicotine-induced convulsions (ED₅₀ 58 mg/kg) and reduced the oxotremorine tremor (ED₅₀ 59 mg/kg). The LD₅₀ of M₁ was 1100 mg/kg orally.

In vitro M₁ was equipotent with nomifensine in inhibiting DA uptake (IC₅₀ 1.5×10^-7 M) and twice as active in inhibiting NA uptake (IC₅₀ 1.1×10^-8 M). In contrast to nomifensine M₁ was also a potent inhibitor of 5-HT uptake (IC₅₀ 3.3×10^-7 M). M₂ and M₃ were less active than M₁ in all experiments.

The results suggest that M₁ may have antidepressant effects in man and may contribute to the clinical effects of nomifensine.