DRUG DEVELOPMENT

药物开发

• 批准号: 6103858
• 负责人: Jeffrey MICHAEL 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/6103858
• 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

For treatment of drug dependencies and associated toxicities, last year's report noted potential for drug development of a phencyclidine (PCP) antagonist based upon the lead candidate PD 128,907, a dopamine D3 receptor agoinst. Additional work has confirmed the predictive efficacy of this and related compounds as PCP blockers and potential atypical antipsychotic agents. We have also demontrated for the first time a role for dopamine D3 receptors in the toxic effects of acutely administered cocaine and methamphetamine. This work based upon classical pharmacological and toxicological methods has led to the following conclusions: D3 receptors are involved in convulsant and lethal effects of cocaine and methamphetamine and D3 receptors may also be involved in psychomotor stimulant abuse. D3 receptor agonists may have clinical utility in the emergency management of stimulant abuse-related toxicities. Ongoing research efforts are involved with mouse strains deficient in dopamine D3 receptors to provide confirmation of the proposed mechanism. Our work on neuroactive steroids has also continued. These compounds, which have been suggested as potential drug abuse treatment agents, have now been shown to have prominent effects against the sensitizing effects of drugs on the nervous system, an action which makes them compelling candidates for both drug abuse treatment and the toxic sequella resulting from drug abuse.

用于治疗药物依赖及相关疾病 毒性，去年的报告指出了药物开发的潜力 基于主要候选 PD 的苯环己哌啶 (PCP) 拮抗剂 128,907，多巴胺D3受体激动剂。额外的工作有 证实了该化合物和相关化合物的预测功效 PCP 阻滞剂和潜在的非典型抗精神病药。我们有 还首次证明了多巴胺 D3 的作用 急性可卡因毒性作用中的受体 甲基苯丙胺。本工作以经典药理学为基础 毒理学方法得出以下结论：D3 受体参与可卡因的惊厥和致命作用 甲基苯丙胺和 D3 受体也可能参与其中 精神运动兴奋剂滥用。 D3 受体激动剂可能具有 兴奋剂应急管理的临床应用 与滥用相关的毒性。正在进行的研究工作涉及 缺乏多巴胺 D3 受体的小鼠品系 确认拟议的机制。我们在神经活性方面的工作 类固醇也持续使用。这些化合物，已被 被建议作为潜在的药物滥用治疗剂，现已被 已被证明对抗过敏作用有显着效果 药物对神经系统的作用，使它们 药物滥用治疗和有毒药物治疗的引人注目的候选人 因滥用药物而产生的后遗症。