ISSN:
1432-2072
Keywords:
Non-tricyclic antidepressants
;
Nomifensine
;
Metabolites
;
Catecholaminergic and serotoninergic activity
;
Noradrenaline, dopamine, serotonin uptake inhibition
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00431726
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