NOVEL NMDA RECEPTOR ANTAGONISTS FOR HIV NEUROINJURY

HIV感染和gp120(HIV包膜)刺激的人巨噬细胞释放毒素，产生过度刺激大脑中NMDA亚型谷氨酸受体(NMDAR)，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，临床可以耐受的NMDA拮抗剂美金刚和一氧化氮(NO)相关物种，如硝酸甘油(NTG)，可以保护神经元/神经胶质混合培养的神经元免受神经损伤。这些结果已经扩展到动物身上，在此基础上，该计划的总体目标是开发既具有美金刚特征又具有无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地相互作用，新药针对的是NMDA受体的NO(即NO等价物)部分，从而减少了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非美金刚化合物。其中两种被选作深入研究的化合物显示了双重作用的NMDA受体阻断，在治疗剂量下没有证据表明全身性低血压。在第二阶段，我们将进一步确定先导化合物的特征，改进结构类似物，并开始临床前开发。具体地说，我们将在重组NMDA受体上对新的非美金刚化合物进行电生理表征，使用原代神经元和体内使用GP120转基因小鼠和啮齿动物脑缺血模型来评估它们对NMDA和艾滋病相关神经元损伤的保护能力。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，以及艾滋病痴呆症。拟议的商业应用：调节NMDA受体的药物有可能治疗艾滋病毒相关性痴呆以及中风、癫痫、创伤和阿尔茨海默病。一个有效的治疗方法将是一个大的公共健康以及市场机会。

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.