Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters.
Aminorex, a metabolite of the cocaine adulterant levamisole, exerts amphetamine like actions at monoamine transporters.
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DOI：
10.1016/j.neuint.2013.11.010
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发表时间：
2014-07
影响因子：
4.2
通讯作者：
Kudlacek O
中科院分区：
文献类型：
--
作者：
Hofmaier T;Luf A;Seddik A;Stockner T;Holy M;Freissmuth M;Ecker GF;Schmid R;Sitte HH;Kudlacek O
我们量化了街头毒品中作为可卡因出售的掺杂物。我们分析了最常见的掺假物左旋咪唑对神经递质转运蛋白的影响。左旋咪唑选择性的差异可以通过同源建模和对接来解释。左旋咪唑的代谢产物Aminorex直接调节神经递质转运蛋白。根据转运蛋白的不同，氨基雷司可以作为阻滞剂或作为抑制剂。安非他明和可卡因等精神兴奋剂是滥用的药物，作用于多巴胺、血清素或去甲肾上腺素的神经递质转运体。这些药物本身就可以引起严重的神经毒性。然而，未经申报而添加到非法化合物中的掺杂物质也会对健康造成额外威胁。街头毒品中最常见的掺杂物之一是驱虫药左旋咪唑。我们测试了左旋咪唑对HEK293细胞中异源表达的神经递质转运蛋白的影响。左旋咪唑在阻断去甲肾上腺素和多巴胺摄取方面的效力比可卡因低100和300倍，并且对5-羟色胺转运体的亲和力非常低。此外，左旋咪唑未引发任何明显的底物外排。由于左旋咪唑和可卡因经常同时给药，我们研究了可能的变构效应;在30 μ M浓度下，左旋咪唑对去甲肾上腺素转运的影响已经很轻微，但并未增强可卡因的抑制作用。左旋咪唑被代谢为氨基雷司（aminorex），这是一种以前上市的厌食药物，被归类为苯丙胺类物质。我们研究了aminorex的摄取抑制和外排诱导特性，发现它对所有三种神经递质转运蛋白产生强烈的影响，其方式类似于安非他明。因此，我们的结论是，虽然掺杂左旋咪唑本身只有适度的影响神经递质转运，其代谢产物氨基雷司本身可能会发挥独特的精神兴奋作用。鉴于左旋咪唑和氨基雷司的半衰期超过可卡因，可以安全地得出结论，在可卡因效应“淡出”后，左旋咪唑/氨基雷司效应“开始”。
We quantified adulterants in street drugs sold as cocaine. We analyzed effects of the most common adulterant levamisole, on neurotransmitter transporters. Differences in the selectivity of levamisole can be explained by homology modelling and docking. Aminorex, a metabolite of levamisole, modulates neurotransmitter transporters directly. Depending on the transporter, aminorex acts as a blocker or as a releaser. Psychostimulants such as amphetamine and cocaine are illicitly used drugs that act on neurotransmitter transporters for dopamine, serotonin or norepinephrine. These drugs can by themselves already cause severe neurotoxicity. However, an additional health threat arises from adulterant substances which are added to the illicit compound without declaration. One of the most frequently added adulterants in street drugs sold as cocaine is the anthelmintic drug levamisole. We tested the effects of levamisole on neurotransmitter transporters heterologously expressed in HEK293 cells. Levamisole was 100 and 300-fold less potent than cocaine in blocking norepinephrine and dopamine uptake, and had only very low affinity for the serotonin transporter. In addition, levamisole did not trigger any appreciable substrate efflux. Because levamisole and cocaine are frequently co-administered, we searched for possible allosteric effects; at 30 μM, a concentration at which levamisole displayed already mild effects on norepinephrine transport it did not enhance the inhibitory action of cocaine. Levamisole is metabolized to aminorex, a formerly marketed anorectic drug, which is classified as an amphetamine-like substance. We examined the uptake-inhibitory and efflux-eliciting properties of aminorex and found it to exert strong effects on all three neurotransmitter transporters in a manner similar to amphetamine. We therefore conclude that while the adulterant levamisole itself has only moderate effects on neurotransmitter transporters, its metabolite aminorex may exert distinct psychostimulant effects by itself. Given that the half-time of levamisole and aminorex exceeds that of cocaine, it may be safe to conclude that after the cocaine effect “fades out” the levamisole/aminorex effect “kicks in”.
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影响因子：
4.4
作者：
Chai, Peter R.;Bastan, William;Babu, Kavita M.
通讯作者：
Babu, Kavita M.
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1111/j.1365-2885.2008.01015.x
发表时间：
2009-04-01
影响因子：
1.3
作者：
Barker, S. A.
通讯作者：
Barker, S. A.
影响因子：
4.8
作者：
Rayes, D;De Rosa, MAJ;Bouzat, C
通讯作者：
Bouzat, C
影响因子：
6.7
作者：
Chang, A.;Osterloh, J.;Thomas, J.
通讯作者：
Thomas, J.