4,4'-Dimethylaminorex (4,4'-DMAR) is a novel psychoactive substance (NPS) that appeared on the illicit drug market in addition to the psychostimulant 4-methylaminorex (4-MAR). Both substances are methylated derivatives of aminorex, an amphetamine-like anorectic used in the 1960ies and withdrawn from the marked due to severe cardiovascular toxicity. The aim of the present study was to characterize the in vitro pharmacological profiles of 4-MAR, 4,4'-DMAR, and 3,4-dimethylaminorex (3,4-DMAR, direx). We assessed norepinephrine (NE), dopamine (DA), and serotonin (5-HT) transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney (HEK) 293 cells. We also assessed monoamine receptor and transporter binding affinities. 4,4'-DMAR potently inhibited all monoamine transporters (IC50<1 μM) with greater potency than 3,4-methlyenedioxymethamphetaime (MDMA) and displayed a higher serotonergic over dopaminergic preference, relatively similar to MDMA (DA transporter / 5-HT transporter inhibition ratio of 0.4 and 0.08 for 4,4'-DMAR and MDMA, respectively). In contrast, 4-MAR preferentially inhibited the NE and DA transporter, exhibiting a pharmacological profile more similar to amphetamine. Both 4-MAR and 4,4'-DMAR were also substrate releasers at the DAT. 3,4-DMAR only weakly inhibited the NE transporter and showed no relevant activity at the DA and 5-HT transporter. Binding affinities of all three aminorex derivatives at various monoamine receptors were negligible (Ki values >2 μM). The in vitro pharmacological profiles indicate that 4,4'-DMAR has comparable psychoactive properties and serotonergic toxicity to MDMA and may be more potent. 4-MAR is a psychostimulant similar to amphetamine or methamphetamine. 3,4-DMAR likely has only weak psychostimulant properties.

中文翻译：

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氨基雷克斯类似物4-MAR，4,4'-DMAR和3,4-DMAR的药理学表征。

4,4'-Dimethylaminorex（4,4'-DMAR）是一种新型的精神活性物质（NPS），除了精神兴奋剂4-methylaminorex（4-MAR）以外，还出现在非法药物市场上。两种物质都是氨力克斯的甲基化衍生物，氨力克斯是一种苯丙胺类厌食症，在1960年代使用，由于严重的心血管毒性而被撤出。本研究的目的是表征4-MAR，4,4'-DMAR和3,4-二甲基氨基雷克斯（3,4-DMAR，direx）的体外药理特性。我们评估了去甲肾上腺素（NE），多巴胺（DA）和5-羟色胺（5-HT）转运蛋白的抑制能力以及转运蛋白转染的人胚肾（HEK）293细胞中单胺的释放。我们还评估了单胺受体和转运蛋白的结合亲和力。4,4'-DMAR有效抑制所有单胺转运蛋白（IC50 < 1μM）具有比3,4-甲撑二氧基甲基苯丙氨酸（MDMA）更高的效能，并且显示出更高的血清素能优于多巴胺能偏好，相对类似于MDMA（4,4'-DMAR和0.4和0.08的DA转运蛋白/ 5-HT转运蛋白抑制比） MDMA）。相反，4-MAR优先抑制NE和DA转运蛋白，表现出与苯丙胺更相似的药理作用。4-MAR和4,4'-DMAR均为DAT的底物释放剂。3,4-DMAR仅弱抑制NE转运蛋白，在DA和5-HT转运蛋白上没有相关活性。在各种单胺受体上所有三种氨基雷克斯衍生物的结合亲和力可以忽略不计（Ki值> 2μM）。体外药理学资料表明4,4' -DMAR具有与MDMA相当的精神活性和血清素能毒性，并且可能更有效。4-MAR是一种精神兴奋药，类似于苯丙胺或甲基苯丙胺。3,4-DMAR可能仅具有弱的精神刺激特性。