DRUG DEVELOPMENT

药物开发

• 批准号: 2571600
• 负责人: J 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/2571600
• 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, and the drug-abuse associated spread of HIV infection in AIDS, previous work by our group has demonstrated the potential for drug development in three major areas: low affinity NMDA antagonists, strychnine-insensitive glycine site antagonists, and benztropine. Having identified last year that ibogaine, a potential broad-based drug abuse therapeutic, was a low affinity NMDA receptor blocker, we have spent the current year identifying other low-affinity ligands that may have similar therapeutic efficacy but are devoid of the behavioral toxicity of ibogaine. We have identified, memantine, as a potential candidate for clinical trials based upon its current safe use in Parkinsonism and our preclinical findings of efficacy. Several analogs of dextromethorphan continue to be evaluated for efficacy and safety. So far, these compounds appear to display a broad margin of safety, compared with other NMDA receptor channel blockers. We have recently discovered a potential new class of compounds that selectively block the behavioral effects of phencylidine (PCP) and related psychotomimetic agents. PD 128,907 is the most selective drug discovered thus far that binds to dopamine D3 receptors. This compound, like the atypical antipsychotic, clozapine, dose- dependently blocks the behavioral effects of the selective PCP-site antagonist, dizocilpine. Like clozapine, PD 128,907 is only marginally effective against dopaminergically-driven behavioral toxicities. Thus, in addition to the potential role of D3 receptor agonists in the treatment of PCP-intoxication and toxicity, this is the first time the D3 receptor population has been directly shown to have relevance to the treatment of schizophrenia. Finally, we have begun work on a novel class of neuroactive steroids. We have shown that these compounds, like NMDA receptor blockers, can protect against the convulsant effects of cocaine that are relatively unresponsive to treatment by standard GABAmimetic drugs like diazepam or phenobarbital. Given the unique activity of these compounds and the previous suggestions that GABA agonists may be useful in the treatment of psychomotor stimulant abuse, we are currently gearing our work toward such an assessment.

用于治疗药物依赖性和相关毒性，以及 毒品滥用艾滋病毒感染在艾滋病中的传播，以前的工作 我们的小组表明了三个药物开发的潜力 主要领域：低亲和力NMDA拮抗剂，不敏感的 甘氨酸位点拮抗剂和苯二甲胺。 去年已经确定 伊博加因（Ibogaine）是一种潜在的基于广泛的药​​物滥用治疗，很低 亲和力NMDA受体阻滞剂，我们已经度过了今年 识别其他可能具有类似治疗性的低亲和力配体 功效，但没有ibogaine的行为毒性。 我们有 鉴定为美容，是基于临床试验的潜在候选者 根据目前在帕金森氏症和我们的临床前发现的安全使用后 功效。 右美沙芬的几个类似物仍然是 评估功效和安全性。 到目前为止，这些化合物似乎 与其他NMDA受体相比，显示大量安全余量 通道阻滞剂。 我们最近发现了一个潜在的新类 有选择地阻断苯乙胺行为效应的化合物 （PCP）和相关的心理剂。 PD 128,907是最大的 迄今为止发现与多巴胺D3受体结合的选择性药物。 这种化合物，例如非典型抗精神病药，氯氮平，剂量 - 依赖地阻止选择性PCP位置的行为效应 拮抗剂，dizocilpine。 像氯氮平一样，PD 128,907仅略有 有效防止多巴胺驱动的行为毒性。 因此， 除了D3受体激动剂在 治疗PCP-内毒和毒性，这是第一次 D3受体人群已直接证明与 精神分裂症的治疗。 最后，我们已经开始在一个新颖的课上工作 神经活性类固醇。 我们已经证明了这些化合物，例如NMDA 受体阻滞剂可以预防可卡因的抽搐作用 标准gabamimetic对治疗的反应相对较不反应 地西p或苯巴比妥等药物。 考虑到这些独特的活动 化合物和先前关于GABA激动剂可能有用的建议 在治疗精神运动刺激滥用方面，我们目前正在训练 我们为这样的评估而进行的工作。