Over the last few decades, the N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR) has received much attention due to their role in brain development and function. They are ionotropic receptors found in nerve cells, gets activated by binding of glutamate and glycine. NMDRs are heteromers composed of NR1 and NR2 subunits. NR2 subunits have four subtypes (A-D) in which NR2A and NR2B are predominant. NMDARs are critical to synaptic transmission, synaptic plasticity and memory function. Dysfunction in NMDAR causes several neuropathological and neurodegenerative disorders including schizophrenia, depression, tinnitus, epilepsy, neuropathic pain, Alzheimer’s disease, Huntington’s, Parkinson’s etc.
The excitotoxic NMDA receptor activation causes acute and chronic neurological disorders. This led to the discovery of many potential clinically relevant therapeutics that aims at blocking excessive NMDA activation without interfering normal NMDA functionality required for normal synaptic transmission and plasticity. To date, several drugs has been developed and tested in different clinical studies and few have achieved FDA approval. Ketamine, methadone, memantine, amantadine, and dextromethorphan are the approved NMDAR antagonist. Amongst them, Ketamine is the strong NMDAR antagonist. Despite their clinical success, these drugs pose many side effects including hallucinations, catatonia, ataxia, nightmares, and memory deficits. These drugs are also addictive that makes it difficult to use for anything that requires prolonged dosing.
Over the time, researchers and drug developers are trying to overcome these side effects. Several emerging therapeutics are in late stage development that promise to provide maximum efficacy with minimum side effects. More than 20 companies are developing drug candidates against this potential target. The major players are Johnson & Johnson (esketamine), Auris Medical (Keyzilen), NeuroRx, Inc. (Cyclurad), Avanir Pharmaceuticals (CERC 301), etc., whose drugs are in late stage of clinical development.
Jyoti Kumari
Associate Analyst
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