AbstractThe pharmacology of dothiepin and its human metabolites, northiaden, dothiepin sulfoxide, and northiaden sulfoxide, has been studied to determine whether the latter contribute to the therapeutic or side effects profile of the parent tricyclic antidepressant. In vitro, dothiepin was a potent noradrenaline and 5‐hydroxytryptamine (5‐HT) uptake inhibitor, while its secondary amine metabolite, northiaden, was selective for noradrenaline. However, the sulfoxide metabolites were almost inactive as uptake inhibitors. Dothiepin and northiaden prevented the ptosis produced by tetrabenazine in mice and reserpine in rats and increased the mobility of mice in the Porsolt test. After repeated administration, both drugs decreased β‐adrenoceptor number and stimulation of the receptor‐linked adenylate cyclase by noradrenaline. Dothiepin had a higher affinity than northiaden for histamine H1, muscarinic and various adrenergic and 5‐HT receptors in vitro, whereas the sulfoxide metabolites were inactive. Overall, the data indicate northiaden almost certainly contributes to the therapeutic actions of dothiepin, but the sulfoxide metabolites do not. However, the latter are also unlikely to produce any side effects. A comparison of dothiepin with other tricyclics revealed important divergences in the profiles of uptake inhibition and receptor affinity. Thus, dothiepin is generally similar to imipramine in its pharmacology, but it differs considerably from amitriptyline and doxepin. © 1992 Wile