Beta-ketoamphetamines: Window to the Neurotoxic Mechanisms of Methamphetamine

 描述(申请人提供)：在美国，“浴盐”滥用已成为严重的公共卫生问题。“浴盐”是一种合成粉末，以象牙波、红鸽或疤痕脸等名义在商业机构和商店合法销售，并被宣传为“合法”或“无害”的快感。“浴盐”是中枢神经系统的兴奋剂，其活性成分包括卡西酮、美卡西酮、甲麻黄酮、甲基酮和3，4-亚甲基二氧基吡喃丙酮(MDPV)。这些药物在化学上被归类为？酮基苯丙胺。越来越多的证据表明，这种药物具有很高的成瘾潜力和对毒品的渴望，这引起了许多监测药物滥用趋势的美国政府机构的担忧，这些机构包括NIDA、白宫毒品沙皇、DEA和司法部。几乎与滥用的增加一样令人担忧的是，缺乏关于它们的作用机制的数据，特别是它们破坏中枢神经系统的能力。这些药物与它们的脱酮苯丙胺同系物在结构上的相似性是惊人的--这些药物之间唯一的区别是苯丙胺上没有脱-酮部分。初步研究表明，该化合物对多巴胺和5-羟色胺神经末梢的神经毒性非常轻微，如果有的话，但它们显著增强了甲基苯丙胺的神经毒性。这一发现令人大吃一惊，因为许多浴盐药物具有被认为对甲基苯丙胺神经毒性至关重要的特征，包括同时刺激DA释放和抑制其摄取和分解代谢，以及核心体温升高。因此，甲氧麻黄酮没有神经毒性这一事实提供了一个极好的机会来确定使其与具有高度神经毒性的甲基苯丙胺相比具有惰性(即从毒性角度看)的结构特征。甲氧麻黄酮的结构包括4位上的β-酮基和甲基。甲基苯丙胺两者都缺乏。因此，这些结构元素中的一个或两个决定了两个基本相同的化合物是神经毒性(即甲基苯丙胺)还是非神经毒性(即甲氧麻黄酮)。从甲氧麻黄酮到甲基苯丙胺的过程中，结构中间体(而不是代谢)是清楚的。如果去掉甲氧麻黄酮的4-CH3基团，则产物为美卡西酮(MC)。如果去除甲麻黄酮β-酮基，则产物为4-甲基-甲基苯丙胺(4-MM)。极少数研究表明，MC对啮齿类动物的DA和5-羟色胺(5-HT)神经末梢造成轻微损害，禁欲的人类MC滥用者DAT持续降低，这可能是神经元损伤的迹象。据我们所知，4-MM还没有在啮齿动物或人类身上进行过研究。因此，CEBRA应用研究的目的是评估MC和4-MM对DA神经末梢的神经毒性作用。这些研究将揭示β-酮基和4-CH3基团对毒性的相对贡献，并为介导甲基苯丙胺神经毒性的结构元素提供一种创新的观点。

 DESCRIPTION (provided by applicant): "Bath salts" abuse has emerged as serious public health concern in the US. "Bath salts" are synthetic powders that are sold legally in commercial establishments and head-shops under such names as Ivory Wave, Red Dove or Scarface and they are promoted as "legal" or "harmless" highs. "Bath salts" are CNS stimulants and the active ingredients include cathinone, methcathinone, mephedrone, methylone and 3,4- methylenedioxypyrovalerone (MDPV). These agents are classified chemically as ß-ketoamphetamines (ß-KA). Emerging evidence of the high addictive potential and craving associated with the ß-KAs has set off alarms of concern at numerous US governmental agencies that monitor drug abuse trends to include NIDA, the White House Drug Czar, DEA and the Department of Justice. Almost as alarming as the rise in abuse of the ß-KAs is the paucity of data on their mechanisms of action and particularly their ability to damage the CNS. The structural analogy of the ß-KAs to their de-keto amphetamine congeners is striking- the only difference between these drugs is the lack of the ß-keto moiety on the amphetamines. Initial studies have indicated that the ß-KAs exert very mild if any neurotoxicity to dopamine and serotonin nerve endings but they significantly enhance methamphetamine neurotoxicity. This finding comes as a great surprise because many of the bath salts drugs possess those characteristics that are thought to be essential for methamphetamine neurotoxicity to include the coincident stimulation of DA release and inhibition of its uptake and catabolism, and elevations in core body temperature. The fact that mephedrone is not neurotoxic therefore offers an excellent opportunity to determine the structural features that render it inert (i.e., from a toxicty perspective) by comparison to the highly neurotoxic methamphetamine. The structure of mephedrone includes a beta-keto group and a methyl group at the 4-position. Methamphetamine lacks both. Therefore, one or both of these structural elements determines whether two essentially identical compounds are neurotoxic (i.e., methamphetamine) or non- neurotoxic (i.e., mephedrone). The structural intermediates (not metabolic) in the progression from mephedrone to methamphetamine are clear. If the 4-CH3 group of mephedrone is removed, the yield is methcathinone (MC). If the beta-keto group of mephedrone is removed, the yield is 4-methyl- methamphetamine (4-MM). A very small number of studies have shown that MC causes mild damage to DA and serotonin (5HT) nerve endings in rodents and abstinent human MC abusers have persistent reductions in the DAT, a possible sign of neuronal damage. 4-MM has not been studied in rodents or humans to the best of our knowledge. Therefore, the goal of studies in this CEBRA application is to assess the ability of MC and 4- MM to cause neurotoxicity to DA nerve endings. The relative contributions of the beta-keto and 4-CH3 groups to toxicity will emerge from these studies and offer an innovative view of the structural elements that mediate methamphetamine neurotoxicity.