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

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• 批准号: 6622494
• 负责人: LAWRENCE S QUANG
• 金额: $ 0.36万
• 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 2003-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6622494
• 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：（申请人提供） γ-羟基丁酸及其化学品的广泛滥用 前体，γ-丁内酯（GBL）和1，4-丁二醇（1，4-BD），已导致 导致危及生命的急性药物过量因为滥用 伽马-羟丁酸及其前体是一种最近才出现的现象， 急性过量的治疗目前是有限的。这项建议的目的是 就申请书内所要求的两个特定研究范畴作出回应 （DA-01-014，“关于伽马--羟丁酸及其前体的研究”） 药物滥用研究所（NIDA）：1。GHB的过量和毒性及其 前体，和2.）* 伽马--羟丁酸及其前体的处理战略。虽然 GHB和GBL被希拉里·J·法瑞斯和萨曼莎·里德·戴特定为非法 2000年《禁止强奸法》（前者现在是联邦附表I药物， 后者是联邦列表I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）。该指定 对生产、销售（饮食中）没有法律的限制 补充剂），或拥有1，4-BD。越来越多的1，4-BD已被 导致严重的危及生命的过量用药和死亡。所以我们 实验室已经优先考虑并将其研究工作集中在1，4-BD上， 目前，这是唯一合法的GHB相关药物。此外，1，4-BD是 唯一一种可以直接与ETOH相互作用的GHB相关药物， 通常与GHB相关药物共同摄入的物质，导致危险 交互.此外，它完全生物转化为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 本申请有三个具体的研究目标。第一个目标是 描述1，4-BD和GHB急性过量后的毒性。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过量和联合急性 1，4-BD和ETOH过量。对于1，4-BD存在潜在有效的解毒剂， 具体而言，以及GHB、GBL和1，4-BD的统称。的解药 1，4-BD是乙醇脱氢酶的特异性拮抗剂 （4-甲基吡唑，Antizol），可阻断体内酶促 1，4-BD生物转化为GHB。GHB GBL和1，4-BD的解毒剂 统称为GABA-B受体的受体拮抗剂（CGP-35348）， GHB特异性受体（NCS-382），GHB的药理作用部位， GBL和1，4-BD。通常，将使用鼠模型（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剂对急性 吸毒过量这项研究的结果将扩大有前途的数据，从试点 本实验室对1，4-BD和GHB的急性毒性也进行了研究 作为新的治疗剂用于其潜在的医疗管理。