Dosulepin

By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug.

Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect.

Main metabolites northiaden, dothiepin sulphoxide and northiaden sulphoxide may also bind to 5HT, α2 and H1 receptors, although with less affinity compared to the parent drug.