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.
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.
