The chemical biology of clinically tolerated NMDA receptor antagonists

Most neuroprotective drugs have failed in clinical trials because of side‐effects, causing normal brain function to become compromised. A case in point 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 itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic‐ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, 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 neurological 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 co‐agonist (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, even although effective in preventing glutamate‐mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open‐channel block with the property of uncompetitive antagonism is the most appealing strategy for therapeutic intervention during excessive NMDAR activation as 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 physiological neurotransmission. Utilizing this molecular strategy of action, we review here the logical process that we applied over the past decade to help 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 moderate‐to‐severe Alzheimer's disease while being well tolerated. Memantine is also currently in trials for additional neurological disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. Additionally, taking advantage of memantine's preferential binding to open channels and the fact that excessive NMDAR activity can be down‐regulated by S‐nitrosylation, we have recently developed combinatorial drugs called NitroMemantines. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order 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 appear to have even greater neuroprotective properties than memantine.