Morin D, Zini R, Urien S, Tillement J P
Service de Pharmacologie, Faculté de Médecine de Paris XII, Creteil, France.
J Pharmacol Exp Ther. 1989 Apr;249(1):288-96.
The interactions of binedaline (binodaline), a new antidepressant drug, and its main metabolites with neurotransmitter receptors and monoamine uptake sites were studied. In receptor binding assays, binedaline was compared to amitriptyline, imipramine, maprotiline and mianserin. Unlike these drugs binedaline did not show any significant affinity for an alpha adrenergic, muscarinic cholinergic, histamine H1 or serotonin2 (5-HT2) receptors. Binedaline and desmethylbinedaline were potent inhibitors of the uptake of norepinephrine in synaptosomes from rat cerebral cortex (Ki = 25 and 29 nM, respectively). Binedaline also inhibited 5-HT uptake with a weak affinity (Ki = 847 nM) but was inactive as an inhibitor of dopamine uptake in synaptosomes from rat striatum (Ki greater than 2 microM). No specific binding was found using [3H]binedaline. After 2 weeks of daily administration of binedaline (20 mg/kg i.p.), the number of beta adrenergic recognition sites labeled with [3H]CGP 12177 remained constant in rat forebrain, as did 5-HT2 receptors and benzodiazepine receptors. In contrast a prolonged treatment with maprotiline (20 mg/kg i.p.) increased the apparent Kd value of [3H]CGP 12177 by 43% and the apparent maximal binding value of [3H]RO 15-1788 by 20% as compared to control. Our results indicate that binedaline is comparable to a tricyclic antidepressant drug in inhibiting the norepinephrine uptake but, however, it is devoid of affinity for neurotransmitter receptors. This probably explains why this drug does not induce the classical side effects of tricyclic antidepressant drugs. These results also suggest that a reduction in beta adrenergic, 5-HT2 or benzodiazepine receptors is not always related to an antidepressant chronic treatment.
研究了新型抗抑郁药联苯达林（双节点林）及其主要代谢产物与神经递质受体和单胺摄取位点的相互作用。在受体结合试验中，将联苯达林与阿米替林、丙咪嗪、马普替林和米安色林进行了比较。与这些药物不同，联苯达林对α肾上腺素能、毒蕈碱胆碱能、组胺H1或5-羟色胺2（5-HT2）受体均未显示出任何显著亲和力。联苯达林和去甲基联苯达林是大鼠大脑皮层突触体中去甲肾上腺素摄取的强效抑制剂（Ki分别为25和29 nM）。联苯达林也以较弱的亲和力抑制5-羟色胺摄取（Ki = 847 nM），但作为大鼠纹状体突触体中多巴胺摄取的抑制剂则无活性（Ki大于2 microM）。使用[3H]联苯达林未发现特异性结合。每天腹腔注射联苯达林（20 mg/kg）2周后，用[3H]CGP 12177标记的β肾上腺素能识别位点数量在大鼠前脑中保持不变，5-HT2受体和苯二氮䓬受体也是如此。相比之下，与对照组相比，用马普替林（20 mg/kg腹腔注射）进行长期治疗使[3H]CGP 12177的表观Kd值增加了43%，[3H]RO 15-1788的表观最大结合值增加了20%。我们的结果表明，联苯达林在抑制去甲肾上腺素摄取方面与三环类抗抑郁药相当，然而，它对神经递质受体缺乏亲和力。这可能解释了为什么这种药物不会诱发三环类抗抑郁药的典型副作用。这些结果还表明，β肾上腺素能、5-HT2或苯二氮䓬受体的减少并不总是与抗抑郁药的长期治疗相关。
