NOVEL NMDA RECEPTOR ANTAGONISTS FOR HIV NEUROINJURY

HIV感染和gp 120（HIV包膜）刺激的人巨噬细胞释放毒素，产生大脑中谷氨酸受体（NMDAR）的NMDA亚型的过度刺激，从而导致神经元损伤。最近，我们和我们的学术合作者，哈佛医学院的Stuart Lipton博士发现，临床耐受的NMDA拮抗剂美金刚和一氧化氮（NO）相关物质如硝酸甘油（NTG）可以保护混合神经元/神经胶质培养物中的神经元免受神经损伤。 这些结果已经扩展到动物，并基于它们，该计划的总体目标是开发具有美金刚和NO相关物种特征的新化合物。由于美金刚与NMDA受体相关的离子通道特异性相互作用，因此新药将NO（即NO等效物）部分靶向NMDA受体，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，我们合成和表征了一些专有的NO-美金刚化合物。选择用于深入研究的这些化合物中的两种表现出双重作用NMDA受体阻滞，在治疗剂量下没有全身性低血压的证据。 在第二阶段，我们将进一步表征先导化合物，改进结构类似物，并开始临床前开发。具体来说，我们将表征新的NO-美金刚化合物的电生理重组NMDA受体，评估其能力，以保护从NMDA和艾滋病相关的神经元损伤，在体外使用原代神经元和在体内使用GP 120转基因小鼠和啮齿动物模型的脑缺血。这些神经保护剂可用于其他神经退行性疾病，如中风、癫痫、创伤和阿尔茨海默病，以及AIDS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。一个有效的治疗方法将是一个巨大的公共卫生以及市场机会。

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.