ISSN:
1432-1912
Keywords:
Mianserin
;
Active metabolites
;
6-Azamianserin
;
Noradrenaline uptake inhibition
;
Alpha receptors
;
Sedation
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary Mianserin, its main metabolites (8-hydroxymianserin, desmethylmianserin and mianserin-N-oxide) and a mianserin analogue, 6-azamianserin (ORG 3770), were compared with regard to effects on monoamine uptake systems, α-adrenoceptors, rat exploratory activity and rat muricidal behaviour. Mianserin and desmethylmianserin inhibited noradrenaline uptake into synaptosomes (IC50's 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 μM) and 8-hydroxymianserin (IC50 9 μM). Dopamine uptake was not affected by any of the compounds tested. All compounds except mianserin-N-oxide blocked presynaptic α-receptors as shown by the potentiation of high-K-induced release of noradrenaline from rat cerebral cortex slices. For mianserin and 6-azamianserin this blockade was shown to be 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. Again, desmethylmianserin was less active than mianserin. None of the compounds appeared to block presynaptic α-receptors in preference to postsynaptic α-adrenoceptors. This was confirmed by the fact that the compounds studied failed to antagonize clonidine-induced sedation in the open field. Clonidine-induced diuresis, however, was stereoselectively inhibited by 6-azamianserin, but the involvement of α2-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 behaviour was inhibited by all compounds except mianserin-N-oxide. The least active was 8-hydroxymianserin. In contrast to mianserin and desmethylmianserin, the blockade of muricidal behaviour by 6-azamianserin was non-specific since it occurred at doses which caused a strong depression of rat open field behaviour. 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. It is concluded that 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 give an answer to the question whether the antidepressant effect of mianserin is solely based upon its interaction with presynaptic α-adrenoceptors or is due to a concomitant blockade of noradrenaline reuptake.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00491478
Permalink
