Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, Org 3770 and its enantiomers.
The neurochemical and autonomic pharmacological profile of 1,2,3,4,10, 14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c]pyrido[2, 3-c] [2] benzazepine [+/-)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H]noradrenaline ([3H]NA) in vitro was weakly affected by (+/-)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (+/-)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by alpha 2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (-)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [3H]rauwolscine to alpha 2-adrenoceptors was inhibited by (+/-)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosin to alpha 1-adrenoceptors was less potently affected by (+/-)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for alpha 1- and alpha 2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (+/-)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (+/-)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (+/-)Org 3770 (pKi = 6.1) and mianserin (pKi = 6.3). Similar data on tryptamine-D, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of alpha 2-adrenoceptors in the therapeutic effects of mianserin and (+/-)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.
Department CNS Pharmacology, Organon International, Oss, The Netherlands.
T H
TH
de Boer
G
G
Maura
M
M
Raiteri
C J
CJ
de Vos
J
J
Wieringa
R M
RM
Pinder
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000078785:Mirtazapine; D009638:Norepinephrine / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism; D015016:Yohimbine / Q000378:metabolism
D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D015016:Yohimbine; D012701:Serotonin; D013134:Spiperone; D011813:Quinuclidinyl Benzilate; D000078785:Mirtazapine; D009638:Norepinephrine; D011224:Prazosin