Beta-ketoamphetamines: Window to the Neurotoxic Mechanisms of Methamphetamine

 描述（由申请人提供）：在美国，“浴盐”滥用已成为严重的公共卫生问题。“浴盐”是合成粉末，在商业机构和总店以象牙波、红鸽子或疤面煞星等名称合法出售，并被宣传为“法律的”或“无害的”兴奋剂。“浴盐”是中枢神经系统兴奋剂，其活性成分包括卡西酮、甲卡西酮、甲氧麻黄酮、甲酮和3，4-亚甲基二氧基吡咯戊酮（MDPV）。这些药物在化学上被归类为α-酮苯丙胺（α-KA）。新出现的证据表明，高上瘾的潜力和渴望与毒品有关的卡已经引发了警报的关注，许多美国政府机构监测药物滥用的趋势，包括国家开发署，白宫毒品沙皇，缉毒局和司法部。几乎与A-KA滥用的增加同样令人担忧的是，关于其作用机制的数据，特别是关于其损害中枢神经系统的能力的数据很少。这种α-KAs与其去酮基安非他明同类物的结构相似性是惊人的--这些药物之间的唯一区别是安非他明上缺少α-酮基部分。最初的研究表明，如果对多巴胺和5-羟色胺神经末梢有任何神经毒性的话，那么B-KA会产生非常轻微的神经毒性，但它们会显著增强甲基苯丙胺的神经毒性。这一发现令人非常惊讶，因为许多浴盐药物具有被认为是甲基苯丙胺神经毒性所必需的特征，包括同时刺激DA释放和抑制其摄取和catalysts，以及核心体温升高。因此，4-甲基甲卡西酮不具有神经毒性的事实为确定使其呈惰性的结构特征（即，从毒性的角度来看）与高度神经毒性的甲基苯丙胺相比。甲氧麻黄酮的结构包括β-酮基和在4位的甲基。冰毒两者都缺乏。因此，这些结构要素中的一个或两个决定了两种基本上相同的化合物是否具有神经毒性（即，甲基苯丙胺）或非神经毒性的（即，甲氧麻黄酮）。从甲氧麻黄酮到甲基苯丙胺的过程中的结构中间体（非代谢）是清楚的。如果去除甲氧麻黄酮的4-CH 3基团，则产率为甲卡西酮（MC）。如果去除甲氧麻黄酮的β-酮基，则产生4-甲基-甲基苯丙胺（4-MM）。极少数研究表明，MC对啮齿动物的DA和5-羟色胺（5-HT）神经末梢造成轻度损伤，戒断的人类MC滥用者的DAT持续减少，这可能是神经元损伤的迹象。据我们所知，尚未在啮齿动物或人类中研究4-MM。因此，CEBRA申请中的研究目标是评估MC和4- MM对DA神经末梢造成神经毒性的能力。β-酮基和4-CH 3基团对毒性的相对贡献将从这些研究中出现，并提供介导甲基苯丙胺神经毒性的结构元素的创新观点。

 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.