Presynaptic alpha-block and inhibition of noradrenaline and 5-hydroxytryptamine reuptake by a series of compounds related to mianserin.
A structure-activity relationship study was undertaken for a variety of structural analogues of the tetracyclic antidepressant mianserin. Presynaptic alpha-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 alpha-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 alpha-blockade unaffected. N-Demethylation and aromatic methyl- or chlorine-substitution reduced presynaptic alpha-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 uptake 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 alpha-blockade and were generally less stringent. For both properties simple additivity relationships appeared to be absent.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D003984:Dibenzazepines / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000494:pharmacology*; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000317:Adrenergic alpha-Antagonists; D003984:Dibenzazepines; D012702:Serotonin Antagonists; D008803:Mianserin; D012701:Serotonin; D009638:Norepinephrine