Presynaptic α-block and inhibition of noradrenaline and 5-hydroxytryptamine reuptake by a series of compounds related to mianserin

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Abstract
A structure-activity relationship study was undertaken for a variety of structural analogues of the tetracyclic antidepressant mianserin. Presynaptic α-blocking activity in vitro was evaluated measuring the potentiation of depolarization-induced noradrenaline (NA) release from rat cerebral cortex slices. Inhibition of NA and 5-hydroxytryptamine reuptake was measured in rat hypothalamic or striatal synaptosomes, respectively. Presynaptic α-blockade was only found in molecules with an overall bent shape. Flat rigid molecules or flexible ones were not active. Six-membered, chair-formed D-rings (containing the -NCH3 moiety) appeared better than 5- or 7-membered ones. Heteroatom substitution, but not hydroxylation or methylation, of the bridge between the two aromatic rings left presynaptic α-blockade unaffected. N-Demethylation and aromatic methyl- or chlorine-subsitution reduced presynaptic α-blockade. In pyridine ring-substituted analogues the localization of the heteroatom appeared to be crucial. 5-Hydroxytryptamine reuptake inhibitory activity was only found in desmethylmianserin. NA reuptake inhibition was found in many mianserin analogues, especially those with an exocyclic -N(CH3)2 moiety. Structure activity relationships for NA reuptake inhibition differed from those for presynaptic α-blockade and were generally less stringent. For both properties simple additivity relationships appeared to be absent.