Beta-ketoamphetamines: Window to the Neurotoxic Mechanisms of Methamphetamine

β-酮苯丙胺：甲基苯丙胺神经毒性机制的窗口

• 批准号: 9036372
• 负责人: Donald M Kuhn
• 金额: $ 19万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036372
• 关键词: Ammonia; Amphetamines; Astrocytes; Bathing; Body Temperature; Catabolism; Central Nervous System Stimulants; Characteristics; Columbidae; Corpus striatum structure; Data; Dopamine; Dose; Drug abuse; Elements; Employee Strikes; Goals; Head; Health; Housing; Human; Justice; Legal; Mediating; Metabolic; Methamphetamine; Mitochondria; Monitor; Names; National Institute of Drug Abuse; Nerve Endings; Neurons; Outcome; Oxygen; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Powder dose form; Proteins; Public Health; Rodent; Salts; Serotonin; Serum; Side; Stress; Structure; Testing; Time; Toxic effect; cathinone; craving; indexing; innovation; methyl group; monomethylpropion; neurochemistry; neurotoxic; neurotoxicity; research study; response; trend; uptake

 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.

 描述（由申请人提供）：“浴盐”滥用已成为美国严重的公共卫生问题。“浴盐”是一种合成粉末，在商业机构和总店以 Ivory Wave、Red Dove 等名称合法销售。或 Scarface，它们被宣传为“合法”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、甲基酮和 3,4-亚甲二氧基吡咯戊酮 (MDPV) 这些药物在化学上被归类为 ß-酮安非他明 (ß-KA)，新出现的证据表明与 ß-KA 相关的高成瘾性和成瘾性引起了人们的关注。许多监测药物滥用趋势的美国政府机构，包括 NIDA、白宫毒品沙皇、DEA 和司法部，几乎与美国国家药品监督管理局 (NIDA) 一样令人震惊。 β-KA 滥用的增加是因为缺乏关于其作用机制的数据，特别是其损害中枢神经系统的能力。 β-KA 与其去酮苯丙胺同源物的结构相似性是惊人的 - 这是它们之间的唯一区别。初步研究表明，β-KA 对多巴胺和苯丙胺具有非常轻微的神经毒性。血清素神经末梢，但它们显着增强甲基苯丙胺的神经毒性，这一发现令人惊讶，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性，包括同时刺激 DA 释放和抑制其吸收和抑制。因此，甲氧麻黄酮不具有神经毒性，这一事实为确定使其惰性的结构特征提供了绝佳的机会。与高度神经毒性的甲基苯丙胺相比，甲氧麻黄酮的结构在 4 位上包含 β-酮基团和甲基苯丙胺，因此，这些结构元素中的一个或两个决定了两种基本相同的化合物。是神经毒性（即甲基苯丙胺）或非神经毒性（即甲氧麻黄酮）从甲氧麻黄酮进展到的结构中间体（非代谢）。如果除去甲麻黄酮的 4-CH3 基团，则得到甲卡西酮 (MC)。 如果除去甲氧麻黄酮的 β-酮基团，则得到 4-甲基-甲基苯丙胺 (4-MM)。少数研究表明，MC 对啮齿类动物的 DA 和血清素 (5HT) 神经末梢造成轻微损害，而戒断人类 MC 滥用者的据我们所知，DAT 是神经元损伤的可能标志，尚未在啮齿动物或人类中进行过研究，因此，本次 CEBRA 应用的研究目标是评估 MC 和 4-MM 的能力。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件提供创新观点。

项目成果

Dissecting the Influence of Two Structural Substituents on the Differential Neurotoxic Effects of Acute Methamphetamine and Mephedrone Treatment on Dopamine Nerve Endings with the Use of 4-Methylmethamphetamine and Methcathinone.

剖析两种结构取代基对急性甲基苯丙胺和甲氧麻黄酮使用 4-甲基甲基苯丙胺和甲卡西酮治疗多巴胺神经末梢的不同神经毒性作用的影响。

• 发表时间: 2017-03
• 作者: Anneken, John H;Angoa;Sati, Girish C;Crich, David;Kuhn, Donald M
• 通讯作者: Kuhn, Donald M