NEUROCHEMICAL AND AUTONOMIC PHARMACOLOGICAL PROFILES OF THE 6-AZA-ANALOGUE OF MIANSERIN, ORG-3770 AND ITS ENANTIOMERS
NEUROCHEMICAL AND AUTONOMIC PHARMACOLOGICAL PROFILES OF THE 6-AZA-ANALOGUE OF MIANSERIN, ORG-3770 AND ITS ENANTIOMERS
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DOI：
10.1016/0028-3908(88)90149-9
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发表时间：
1988-04-01
影响因子：
4.7
通讯作者：
PINDER, RM
中科院分区：
文献类型：
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作者：
DEBOER, T;MAURA, G;PINDER, RM
本文比较了1，2，3，4，10，14 b-六氢-2-甲基吡嗪并[2，1-a]吡啶并[2，3-c][2]苯并氮杂卓（±）3770和相关抗抑郁药米安色林的神经化学和自主药理学特征。[~ 3 H]去甲肾上腺素（[~ 3 H]NA）在体外的摄取受（±）α 3770（pKi= 5.6）的影响较小，米安色林（pKi= 7.4）的影响较小。（±）α 3770和米安色林均能促进脑片[3 H]NA的释放。α_2肾上腺素能受体介导的NA对[~ 3 H]NA和[~ 3 H]5-HT释放的影响可被（+）α_3770拮抗，pKi值分别为8.4和8.1。然而，（-）α 3770仅拮抗NA对[3 H]5-HT释放的影响（pA 2 = 7.7）。[~ 2 H]萝芙木碱与α_2-肾上腺素能受体的结合被（±）α_3770和米安色林以相同的亲和力抑制（pKi= 7.0），而[~ 3 H]哌唑嗪与α_1-肾上腺素能受体的结合被（±）α_3770（pKi= 6.4）的影响小于米安色林（pKi= 7.1）。大鼠输精管α1和α2肾上腺素能受体也有类似的差异。[~ 3 H]米安色林与5-HT_2受体的结合受（±）β_3770（pKi= 8.1）的阻断作用弱于米安色林（pKi= 9.4），而[~ 3 H]美托咪胺与组胺-1受体的结合受（±）β_3770（pKi= 9.3）的影响强于米安色林（pKi= 8.75）。[~ 3 H]奎宁环基二苯乙酸酯与毒蕈碱胆碱能受体的结合被（±）α 3770（pKi= 6.1）和米安色林（pki= 6.3）阻断。色胺-d，组胺-1和毒蕈碱胆碱能受体在离体器官中获得类似的数据。α_2-肾上腺素能受体阻滞剂在米安色林和（±）α_2-肾上腺素能受体拮抗剂治疗抑郁症的作用中起重要作用，可能不包括抑制NA摄取的作用。
The neurochemical and autonomic pharmacological profile of l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]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 vitrowas 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 byα2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKivalues 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 [2H]rauwolscine toα2-adrenoceptors was inhibited by (±)Org 3770 and mianserin with identical affinity (pKi= 7.0), whereas the binding of [3H]prazosine toα1-adrenoceptors was less potently affected by (±)Org 3770 (pKi= 6.4) than by mianserin (pKi= 7.1). A similar difference was found for α1- and α2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2receptors 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 ofα2-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.