NOVEL NMDA RECEPTOR ANTAGONISTS FOR HIV NEUROINJURY

治疗 HIV 神经损伤的新型 NMDA 受体拮抗剂

• 批准号: 2869946
• 负责人: YUQIANG WANG
• 金额: $ 36.59万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2869946
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; HIV envelope protein gp120; NMDA receptors; confocal scanning microscopy; drug design /synthesis /production; drug screening /evaluation; electrophysiology; genetically modified animals; inhibitor /antagonist; laboratory mouse; laboratory rat; neuroprotectants; nitric oxide; nuclear magnetic resonance spectroscopy; site directed mutagenesis; tissue /cell culture

HIV-infected and gp120 (HIV envelope)-stimulated human macrophages release toxins that produce excessive stimulation of the NMDA subtype of glutamate receptor (NMDAR) in the brain, with consequent neuronal injury. Recently, we and our academic collaborator, Dr. Stuart Lipton, Harvard Medical School, found that the clinically-tolerated NMDA antagonist memantine and nitric oxide (NO)-related species such as nitroglycerin (NTG) can protect neurons in mixed neuronal/glial cultures from neuroinjury. These results have been extended to animals and based on them, the overall goal of this program is to develop new compounds that have the features of both memantine and NO-related species. Because memantine specifically interacts with the ion channel associated with the NMDA receptor, the new drugs target the NO (i.e. NO-equivalent) moiety to the NMDA receptor, thus reducing potential systemic side-effects (such as hypotension) of NO-related drugs. In Phase I we synthesized and characterized a number of proprietary NO-memantine compounds. Two of these compounds selected for in-depth study demonstrated dual action NMDA-receptor blockage with no evidence of systemic hypotension at therapeutic doses. In phase II we will further characterize the lead compounds and make improved structural analogs and begin preclinical development. Specifically we will characterize the novel NO-memantine compounds electrophysiologically on recombinant NMDA receptors, evaluate their capacity to protect from NMDA and AIDS-related neuronal damage in vitro using primary neurons and in vivo using GP120-transgenic mice and rodent models of cerebral ischemia. These neuroprotective agents may be useful in other neurodegenerative conditions such as stroke, epilepsy, trauma, and Alzheimer's disease, in addition to AIDS dementia. PROPOSED COMMERCIAL APPLICATIONS: Drugs that modulate the NMDA receptor have potential for the treatment of HIV-associated dementia as well as stroke, epilepsy, trauma, and Alzheimer's disease. An effective therapy will be a large public health as well as market opportunity.

HIV感染和gp120 （HIV包膜）刺激的人巨噬细胞释放毒素，对大脑中谷氨酸受体（NMDAR）的NMDA亚型产生过度刺激，从而导致神经元损伤。最近，我们和我们的学术合作伙伴，哈佛医学院的Stuart Lipton博士发现临床耐受的NMDA拮抗剂memantine和一氧化氮（NO）相关物质如硝酸甘油（NTG）可以保护混合神经元/胶质培养中的神经元免受神经损伤。这些结果已经扩展到动物，并以此为基础，该计划的总体目标是开发具有美金刚和一氧化氮相关物种特征的新化合物。由于美金刚特异性地与NMDA受体相关的离子通道相互作用，新药物靶向NMDA受体的NO（即NO当量）部分，从而减少NO相关药物的潜在全身副作用（如低血压）。在第一阶段，我们合成并表征了一些专有的no -美金刚化合物。其中两种化合物被选择用于深入研究，显示出双重作用的nmda受体阻断，在治疗剂量下没有全身性低血压的证据。在II期，我们将进一步表征先导化合物，制造改进的结构类似物，并开始临床前开发。具体来说，我们将在重组NMDA受体上对新型no -美金刚化合物进行电生理表征，在体外用原代神经元，在体内用gp120转基因小鼠和脑缺血啮齿动物模型评估其保护NMDA和艾滋病相关神经元损伤的能力。这些神经保护剂可能对其他神经退行性疾病有用，如中风、癫痫、创伤和阿尔茨海默病，除了艾滋病痴呆。拟议的商业应用：调节NMDA受体的药物具有治疗hiv相关痴呆以及中风、癫痫、创伤和阿尔茨海默病的潜力。一种有效的疗法将是一个巨大的公共卫生以及市场机会。