Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: A pharmacological strategy for treating stimulant abuse
Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: A pharmacological strategy for treating stimulant abuse
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DOI：
10.1002/(sici)1098-2396(20000301)35:3
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发表时间：
2000-03-01
期刊：
影响因子：
2.3
通讯作者：
Rice, KC
中科院分区：
文献类型：
--
作者：
Rothman, RB;Partilla, JS;Rice, KC
在美国，滥用甲基苯丙胺和其他类似安非他明的兴奋剂是一个日益严重的问题。甲基安非他明是12种跨膜蛋白的底物，这些蛋白作为生物胺多巴胺（DA）、血清素（5-HT）和去甲肾上腺素（NE）的转运体。CNS DA释放的增加被认为介导甲基苯丙胺的成瘾效应，而外周神经系统和CNS中NE释放的增加被认为介导其心血管效应。甲基苯丙胺对多巴胺能和血清素能神经的神经毒性作用需要将甲基苯丙胺运输到神经末梢。因此，甲基苯丙胺转运到神经末梢是产生甲基苯丙胺相关药理学和毒理学效应的关键第一步。一个单一的分子实体可以阻断甲基苯丙胺在三种生物胺转运体上的转运，可能起到神经化学中和甲基苯丙胺的作用。理想情况下，这种药物在所有三种转运蛋白上都是一种高亲和力的缓慢解离剂，并且可以作为长效储备药物，例如GBR12909的类似物。作为开发这种药物的第一步，我们建立了一种体外实验，可以选择性地检测转运体底物，并使用该实验来分析一种先导化合物，茚三唑啉，在DA， 5-HT和NE转运体上阻断甲基安非他明和MDMA释放作用的能力。这里报告的主要发现是，茚丙林阻断了甲基苯丙胺和MDMA释放这些神经递质的能力。(C)出版2000 Wiley-Liss， Inc。
The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a growing problem in the United States. METH is a substrate for the 12-transmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased release of CNS DA is thought to mediate the addictive effects of METH, whereas increased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial first step in the production of METH-associated pharmacological and toxicological effects. A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. This agent would ideally be a high-affinity slowly dissociating agent at all three transporters, and also be amenable to formulation as a long-acting depot medication, such as has been accomplished with an analog of GBR12909. As a first step towards developing such an agent, we established an in vitro assay which selectively detects transporter substrates and used this assay to profile the ability of a lead compound, indatraline, to block the releasing effects of METH and MDMA at the DA, 5-HT, and NE transporters. The major finding reported here is that indatraline blocks the ability of METH and MDMA to release these neurotransmitters. (C) Published 2000 Wiley-Liss, Inc.