Clinically Tolerated Strategies for NMDA Receptor Antagonism

Many potentially neuroprotective drugs have failed in human clinical trials because of side effects that cause normal brain function to become compromised. An important example concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids such as glutamate is thought to contribute to neuronal damage in many neurologic disorders ranging from acute hypoxic–ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, HIV-associated dementia, multiple sclerosis, glaucoma, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurologic diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor–channel complex. These include drugs acting at the agonist (NMDA) or coagonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site, where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, From: The Receptors: The Glutamate Receptors even though they are effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block, a form of uncompetitive antagonism, is the most appealing strategy for therapeutic intervention during excessive NMDAR activation because this action of blockade; requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiologic neurotransmission. As an alternative strategy, genetic manipulation of NR3 subunits can reduce glutamateinduced currents and Ca2+ influx through NMDARs without completely blocking their activation. Based on this molecular strategy of action, this chapter reviews the logical process that was applied over the last decade to develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderateto- severe Alzheimer’s disease while being well tolerated. Memantine is also in trials for additional neurologic disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. In addition, taking advantage of memantine’s preferential binding to open channels and the act that excessive NMDAR activity can be downregulated by S-nitrosylation, combinatorial drugs called NitroMemantine have recently been developed. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs to avoid systemic side effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies they appear to have even greater neuroprotective properties than memantine.