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Comparative pharmacology of mianserin its main metabolites and 6 aza mianserin

Comparative pharmacology of mianserin its main metabolites and 6 aza mianserin

Naunyn-Schmiedeberg's Archives of Pharmacology 319(1): 48-55

Mianserin, its main metabolites (8-hydroxymianserin, desmethylmianserin and mianserin-N-oxide) and a mianserin analog, 6-azamianserin (ORG 3770), were compared with regard to effects on monoamine uptake systems, .alpha.-adrenoceptors, rat exploratory activity and rat muricidal behavior. Mianserin and desmethylmianserin inhibited noradrenaline (nonepinephrine] uptake into synaptosomes (IC50 [median inhibitory concentration] 30 and 60 nM, respectively), whereas the other compounds were much less active. Synaptosomal serotonin uptake was only inhibited to a small extent by desmethylmianserin (IC50 6 .mu.M) and 8-hydroxymianserin (IC50 9 .mu.M). Dopamine uptake was not affected by any of the compounds tested. All compounds except mianserin-N-oxide blocked presynaptic .alpha.-receptors, as shown by the protentiation of high-K-induced release of noradrenaline from rat cerebral cortex slices. For mianserin and 6-azamianserin this blockade was stereoselective. Desmethylmianserin was less potent than mianserin. Binding of 3H-dihydroergocryptine to rat cerebral cortex membranes was inhibited by all compounds except mianserin-N-oxide. Desmethylmianserin was less active than mianserin. None of the compounds appeared to block presynaptic .alpha.-receptors in preference to postsynaptic .alpha.-adrenoceptors. The compounds studied failed to antagonize clonidine-induced sedation in the open field. Clonidine-induced diuresis was stereoselectively inhibited by 6-azamianserin, but the involvement of .alpha.2-receptors in this phenomenon is not firmly established. Antihistamine properties as determined by 3H-mepyramine binding to rat brain membranes were most pronounced for 6-azamianserin. Mianserin was slightly less potent and desmethylmianserin and 8-hydroxymianserin were 10 and 30 times less potent than mianserin, respectively. Muricidal behavior was inhibited by all compounds except mianserin-N-oxide. The least active was 8-hydroxymianeserin. In contrast to mianserin and desmethylmianserin, the blockade of muricidal behavior by 6-azamianserin was nonspecific, since it occurrred at doses which caused a strong depression of rat open field behavior. Mianserin was less sedative than 6-azamianserin, whereas the metabolites showed no sedative effects at doses up to 32 mg/kg in the open field The main metabolites of mianserin possess pharmacological properties which may add to the therapeutic potential of mianserin. Clinical testing of 8-hydroxymianserin and 6-azamianserin may indicate whether the antidepressant effect of mianserin is solely based upon its interaction with presynaptic .alpha.-adrenoceptors or is due to a concomitant blockade of noradrenaline reuptake.

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Accession: 004997523

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PMID: 6287300

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