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: 6185803
• 负责人: YUQIANG WANG
• 金额: $ 38.41万
• 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/6185803
• 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; 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）刺激的人类巨噬细胞释放毒素，从而产生过度刺激大脑中谷氨酸受体（NMDAR）的NMDA亚型，并导致神经元损伤。最近，我们和我们的学术合作者，哈佛医学院的Stuart Lipton博士发现，临床耐受性的NMDA拮抗剂美容和硝酸氧化物（NO）相关物种（例如硝酸甘油（NTG））可以保护来自神经毒素的神经/胶质培养基中混合神经元中的神经元。 这些结果已扩展到动物，并基于它们，该程序的总体目标是开发具有纪念品和无相关物种特征的新化合物。由于美灵氨酸特异性与与NMDA受体相关的离子通道相互作用，因此新药物的目标是NO（即无等效）与NMDA受体的部分，从而降低了无相关药物的潜在全身副作用（例如低血压）。在第一阶段，我们合成并表征了许多专有的无膜化合物。这些用于深入研究的化合物中有两种表明双重作用NMDA受体阻塞，没有治疗剂量时系统性低血压的证据。 在第二阶段，我们将进一步表征铅化合物并改善结构类似物并开始临床前的发展。具体而言，我们将在重组NMDA受体上进行电生理学的新型无绝不会化合物来评估其在体外使用原发性神经元和体内使用GP120-Transgenic-Transgenic Miles和Interbe Interbe Interbral Ischemia的INMDA和AIDS与AIDS相关的神经元损伤的能力。这些神经保护剂在其他神经退行性疾病（例如中风，癫痫，创伤和阿尔茨海默氏病）中也可能有用，此外也可能对艾滋病痴呆症。拟议的商业应用：调节NMDA受体的药物具有治疗与HIV相关痴呆以及中风，癫痫，创伤和阿尔茨海默氏病的潜力。有效的疗法将是大型公共卫生和市场机会。