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首页> 外文期刊>CNS drug reviews >Preclinical and clinical pharmacology of DOV 216,303, a 'triple' reuptake inhibitor.
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Preclinical and clinical pharmacology of DOV 216,303, a 'triple' reuptake inhibitor.

机译：DOV 216,303（一种“三重”再摄取抑制剂）的临床前和临床药理作用。

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DOV 216,303 [(+/-)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as "triple" reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [(3)H]NE, [(3)H]5-HT, and [(3)H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC(50) values of approximately 20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well-tolerated. Furthermore, both C(max) and AUC values were dose-proportional between 5-150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC(50) values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM-D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.
机译：DOV 216,303 [（+/-）-1-（3,4-二氯苯基）-3-氮杂双环-[3.1.0]己烷盐酸盐]是一类化合物的原型，被称为“三重”再摄取抑制剂。这类化合物抑制去甲肾上腺素（NE），5-羟色胺（5-HT）和多巴胺（DA）的再摄取，这三种神经递质与主要的抑郁症关系最密切。 DOV 216,303抑制[（3）H] NE，[（3）H] 5-HT和[（3）H] DA摄取至相应的人类重组转运蛋白（在HEK 293细胞中表达），IC（50）值为分别约为20、14和78 nM。 DOV 216,303在预测抗抑郁活性的测试中很活跃，包括小鼠强迫游泳测试和丁苯那嗪诱导的上睑下垂和运动性抑郁症的逆转。 DOV 216,303在动物体内的药效学，药代动力学和毒理学特征促使我们开展临床研究。在使用正常志愿者进行的单剂量和多剂量研究中，DOV 216,303是安全且耐受性良好的。此外，C（max）和AUC值在5-150 mg之间与剂量成正比。剂量> 10 mg的DOV 216,303的血浆浓度超过了抑制生物胺再摄取的IC（50）值。在旨在探索DOV 216,303在抑郁症患者中的安全性和耐受性的II期研究中，患者接受了100 mg DOV 216,303（50 mg b.i.d.）或40 mg西酞普兰（20 mg，b.i.d.）治疗两周。在这项研究中未使用安慰剂组，因为几个机构审查委员会要求对严重抑郁的患者进行有效控制。与基线分数相比，DOV 216,303和西酞普兰组均观察到HAM-D分数随时间变化的减少（主要结局指标）。各治疗组之间的副作用无明显差异。这些发现提供了具有临床意义的抗抑郁作用的初步证据，该分子具有一种能够抑制与主要抑郁症最密切相关的三种递质的分子。

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