Adrenoreceptor interactions of the enantiomers and metabolites of mianserin: are they responsible for the antidepressant effect?

Mianserin is a tetracyclic antidepressant whose postulated mechanism of action involves release of noradrenaline mediated via cortical alpha 2-adrenergic autoreceptor blockade. This property resides stereoselectively in the S(+)-enantiomer of mianserin, which is also more potent in behavioural tests indicative of antidepressant activity, and in the reversal of clonidine-induced effects. Cortical receptor binding studies have indicated that although a similar stereoselectivity prevails for the inhibition of both alpha 2-binding (clonidine) and alpha 1-binding (prazosin), mianserin and its enantiomers are more potent antagonists at alpha 2- than at alpha 1-binding sites. However, no stereoselectivity is apparent for the antagonism of cortical alpha 2-heteroreceptors controlling serotonin release. Following chronic administration, (+/-)- and S(+)-mianserin, but not the R(-)-enantiomer, produce functional supersensitivity at alpha 2-autoreceptors which is unaccompanied by changes in clonidine binding. Neither mianserin nor its enantiomers alter the sensitivity of alpha 2-heteroreceptors following chronic administration. Like mianserin and its S(+)-enantiomer, but unlike R(-)-mianserin and the 8-hydroxy metabolite, the desmethyl metabolite inhibits noradrenaline uptake in vitro. 8-hydroxymianserin and, to a lesser extent, desmethylmianserin release noradrenaline from cortical slices via alpha 2-autoreceptor antagonism, but only the 8-hydroxy metabolite blocks alpha 2-autoreceptors and alpha 2-heteroreceptors in synaptosomal preparations. It is likely that S(+)-mianserin, desmethylmianserin, and 8-hydroxymianserin contribute substantially to the overall facilitating effect of mianserin on noradrenergic transmission in vivo. As yet it is unclear whether this effect is exclusively responsible for the antidepressant activity of mianserin or whether the stereoselectivity also shown by the mianserin enantiomers towards serotonin receptors plays a complementary role.