Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor
Preclinical and clinical pharmacology of DOV 216,303, a "triple" reuptake inhibitor
复制标题
DOI：
10.1111/j.1527-3458.2006.00123.x
复制
发表时间：
2006-06-01
期刊：
影响因子：
--
通讯作者：
Lippa, Arnold
中科院分区：
文献类型：
--
作者：
Skolnick, Phil;Krieter, Philip;Lippa, Arnold
DOV 216，303 [（+/-）-1-（3，4-二氯苯基）-3-氮杂双环-[3.1.0]己烷盐酸盐]是一类被称为“三重”再摄取抑制剂的化合物的原型。这些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，这三种神经递质与重度抑郁症关系最密切。DOV 216，303抑制[H-3]NE、[H-3]5-HT和[H-3]DA摄取至相应的人重组转运蛋白（在HEK 293细胞中表达），IC 50值分别为20、14和78 nM。DOV 216，303在预测抗抑郁活性的试验中具有活性，包括小鼠强迫游泳试验和丁苯那嗪诱导的上睑下垂和运动抑制的逆转。DOV 216，303在动物中的药效学、药代动力学和毒理学特征促使我们启动临床研究。在使用正常志愿者的单次和多次给药研究中，DOV 216，303安全且耐受性良好。此外，在5-150 mg之间，C-max和AUC值均与剂量成比例。DOV 216，303在剂量> 10 mg时的血浆浓度超过生物胺再摄取抑制的IC 50值。在一项旨在探索DOV 216，303在抑郁个体中的安全性和耐受性的11期研究中，患者接受100 mg DOV 216，303（50 mg b.i.d.）或40 mg西酞普兰（20 mg，b.i.d.）住两个星期.本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个体给予活性对照。与基线评分相比，DOV 216，303和西酞普兰组的HAM-D评分（主要结果测量）均观察到时间依赖性降低（p < 0.0001）。治疗组间的副作用无显著差异。这些发现提供了一个具有临床意义的抗抑郁作用的初步证据，该分子能够抑制与重度抑郁症最密切相关的三种递质。
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 [H-3]NE, [H-3]5-HT, and [H-3]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC50 values of similar to 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 IC50 values for inhibition of biogenic amine reuptake. In a Phase 11 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 arrns. 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.