Enzyme & Receptor Antagonists of GHB, GBL & 1, 4-BD

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• 批准号: 6447759
• 负责人: LAWRENCE S QUANG
• 金额: $ 6.3万
• 依托单位: MCPHS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-10 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6447759
• 关键词: GABA receptor; acute disease /disorder; alcohol dehydrogenase; anticonvulsants; antidotes; behavioral /social science research tag; biotransformation; butyrolactone; cytotoxicity; diol; disease /disorder model; drug abuse chemotherapy; drug interactions; drug metabolism; drug receptors; enzyme inhibitors; ethanol; gamma hydroxybutyrate; inhibitor /antagonist; laboratory mouse; neurochemistry; nonhuman therapy evaluation; overdose; pharmacokinetics; substance abuse related behavior

DESCRIPTION: (provided by applicant) The widespread abuse of gamma-hydroxybutyrate (GHB) and its chemical precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), has resulted in escalating episodes of life-threatening acute overdoses. Because abuse of GHB and its precursors is a recently evolving phenomenon, treatment strategies for acute overdoses are currently limited. The objectives of this proposal are to address two specific research areas solicited in the request for application (DA-01-014, "Research on GHB and Its Precursors") issued by the National Institute on Drug Abuse (NIDA): 1.) overdose and toxicity of GHB and its precursors, and 2.) treatment strategies for GHB and its precursors. Although GHB and GBL were made illegal by the Hillary J. Farias and Samantha Reed Date Rape Prohibition Act of 2000 (the former is now a federal schedule I drug, and the latter is a federal list I chemical), 1,4-BD is currently recognized as a Class I Health Hazard (a potentially life-threatening hazard). This designation imposes no legal restrictions on the manufacture, distribution (in dietary supplements), or possession of 1,4-BD. Increasingly, 1,4-BD has been responsible for severe life-threatening overdoses and deaths. Thus, our laboratory has prioritized and focused its research efforts on 1,4-BD, which is currently the only legally available GHB-related drug. Additionally, 1,4-BD is the only GHB-related drug that can directly interact with ETOH, the most commonly coingested substance with GHB-related drugs, leading to dangerous interactions. Furthermore, its complete biotransformation to GHB permitted us the unique opportunity to study indirectly GHB's interactions with ETOH and GABA-B and GHB receptors. This application has three specific research aims. The first aim is to characterize 1,4-BD and GHB toxicity after acute overdoses. The second aim is to study potential interactions of 1,4-BD and GHB with ETOH. The third aim is to investigate potential antidotes for acute 1,4-BD overdose and combined acute 1,4-BD and ETOH overdose. Potentially effective antidotes exist for 1,4-BD, specifically, and for GHB, GBL, and 1,4-BD collectively. The antidote for 1,4-BD specifically is an enzyme antagonist of alcohol dehydrogenase (4-methylpyrazole, Antizol), which may block in vivo enzymatic biotransformation of 1,4-BD to GHB. The antidotes for the GHB, GBL, and 1,4-BD collectively are receptor antagonists of GABA-B receptors (CGP-35348) and GHB-specific receptors (NCS-382), the sites of pharmacologic action of GHB, GBL, and 1,4-BD. In general, a murine model (CD-l mice) will be used to assess the acute effects of 1,4-BD, GHB, and ETOH on behavioral (open field locomotion test), neuromuscular (righting reflex, rotarod test, grip strength test), and biochemical processes (blood 1,4-BD and GHB levels). This murine model will also be used to study the effects of potential therapeutic agents for acute overdoses. The results of this study will expand upon promising data from pilot studies performed in this laboratory on acute 1,4-BD and GHB toxicity as well as novel therapeutic agents for its potential medical management.

描述：（由申请人提供） γ-羟基丁酸酯（GHB）及其化学物质的广泛滥用 前体，γ-丁内酯（GBL）和1,4-丁二醇（1,4-BD），已产生 危及生命的急性药物过量事件不断升级。因为滥用 GHB 及其前体是最近演变的一种现象，治疗策略 目前对于急性药物过量的治疗是有限的。该提案的目标是 解决申请请求中提出的两个具体研究领域 （DA-01-014，“GHB及其前体的研究”）由国家 药物滥用研究所 (NIDA)：1.) GHB 及其毒性的过量和毒性 前体，以及 2.) GHB 及其前体的治疗策略。虽然 GHB 和 GBL 被 Hillary J. Farias 和 Samantha Reed Date 定为非法 2000 年《禁止强奸法》（前者现已成为联邦一级药物，并且 后者是联邦 I 类化学品），1,4-BD 目前被认为是 I 类健康危害（潜在危及生命的危害）。这个指定 对生产、分销（在膳食中）没有施加任何法律限制 补充剂），或拥有 1,4-BD。 1,4-BD 越来越多地被 造成严重危及生命的药物过量和死亡。因此，我们的 实验室将其研究工作重点放在1,4-BD上，这是 目前唯一合法可用的 GHB 相关药物。此外，1,4-BD 是 唯一能与 ETOH 直接相互作用的 GHB 相关药物， 通常与 GHB 相关药物混合使用，导致危险 互动。此外，其完全生物转化为 GHB 使我们能够 间接研究 GHB 与 ETOH 相互作用的独特机会 GABA-B 和 GHB 受体。 该应用程序具有三个具体的研究目标。第一个目标是 表征急性过量服用后 1,4-BD 和 GHB 的毒性。第二个目标是 研究 1,4-BD 和 GHB 与 ETOH 的潜在相互作用。第三个目标是 研究急性 1,4-BD 过量用药和联合急性用药的潜在解毒剂 1,4-BD 和 ETOH 过量。存在针对 1,4-BD 的潜在有效解毒剂， 具体而言，对于 GHB、GBL 和 1,4-BD 统称。解毒剂为 1,4-BD 特别是乙醇脱氢酶的酶拮抗剂 （4-甲基吡唑，Antizol），可能会阻断体内酶促 1,4-BD 生物转化为 GHB。 GHB、GBL 和 1,4-BD 的解毒剂 统称为 GABA-B 受体 (CGP-35348) 的受体拮抗剂和 GHB 特异性受体 (NCS-382)，GHB 药理作用位点， GBL 和 1,4-BD。一般而言，将使用小鼠模型（CD-1小鼠）来评估 1,4-BD、GHB 和 ETOH 对行为（旷场运动）的急性影响 测试）、神经肌肉（翻正反射、转棒测试、握力测试）和 生化过程（血液 1,4-BD 和 GHB 水平）。该小鼠模型将 也可用于研究潜在治疗药物对急性发作的影响 服药过量。这项研究的结果将扩展来自试点的有希望的数据 该实验室还对急性 1,4-BD 和 GHB 毒性进行了研究 作为潜在医疗管理的新型治疗剂。