DRUG DEVELOPMENT

药物开发

• 批准号: 6431918
• 负责人: JEFFREY M WITKIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431918
• 关键词: NMDA receptors; antiparkinson drugs; behavioral habituation /sensitization; benztropine; cocaine; dextromethorphan; diazepam; drug abuse chemotherapy; drug addiction antagonist; drug design /synthesis /production; drug screening /evaluation; ibogaine; phencyclidine; phenobarbital; psychopharmacology; psychotomimetic drug; reinforcer; steroids; strychnine

Our group has continued its efforts to discover an efficacious and safe pharmacological treatment for acute and chronic cocaine poisoning. For this reporting period, we have identified a drug in clinical practice that has efficacy in our animal models of drug-resistant cocaine seizures. Chlormethiazole protected against acute cocaine seizures and lethality and blocked the expression of sensitization to the convulsant effects of cocaine. Further, chlormethiazole prevented the neural adaptation that resulted from repeated daily exposure to cocaine. Importantly the pharmacological profile of chlormethiazole was superior to that of the benzodiazepines, clonazepam and diazepam, which were of limited efficacy and had narrow therapeutic indices. The results of these studies predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse for which no specific treatment has yet been identified. Our group has also begun investigations into the mechanisms underlying increased sensitivity to the toxic effects of cocaine with repeated drug exposure. In this area we have identified adenosine receptors as an important target. Both the behavioral effects and the toxic effects of adenosine ligands is enhanced with repeated cocaine treatment. Further studies are underway to determine the changes in dopamine D3 receptors in ventral striatum and the neurochemical changes in this and other brain areas that are associated with the increased toxicity to cocaine as well as the protection that is conferred by D3 receptor agonists as we reported earlier. Changes in gene expression and proteins in brains of sensitized animals are being explored based upon our pharmacological data of protective efficacies of pharmacologically selective agents.

我们的小组继续努力发现急性和慢性可卡因中毒的有效且安全的药理治疗方法。 在此报告期间，我们已经确定了一种临床实践中的药物，该药物在我们的耐药可卡因癫痫发作的动物模型中具有功效。 铁甲烷可免受急性可卡因癫痫发作和致死性，并阻止了敏化表达对可卡因的抽搐作用。此外，金甲唑防止了每天反复暴露于可卡因导致的神经适应。 重要的是，金甲唑的药理特征优于苯二氮卓类药物，氯硝西epam和地西epa，它们的功效有限且具有狭窄的治疗指数。 这些研究的结果预测了金甲唑对可卡因滥用生命并发症治疗可卡因并发症的潜在效用，尚未确定特定的治疗方法。 我们的小组还开始研究对可卡因的毒性作用提高的机制，并反复暴露于可卡因的毒性作用。 在这一领域，我们将腺苷受体确定为重要靶标。 通过重复可卡因治疗，腺苷配体的行为作用和毒性作用都得到了增强。 正在进行进一步的研究，以确定腹侧纹状体中多巴胺D3受体的变化以及与可卡因毒性增加有关的该大脑和其他大脑区域的神经化学变化，以及D3受体激动剂的保护，如我们之前报道的D3受体激动剂所提供的保护。 根据我们的药理学选择性剂的保护作用数据，正在探索敏化动物大脑中基因表达和蛋白质的变化。