Series of compounds for selectively potentiating N-methyl-D-aspartate (NMDA) receptor subunit NR2C for treating central nervous system impairment.
- Selectivity for NR2C may reduce possibility of adverse side effects.
N-methyl-D-aspartate (NMDA) receptors are widely dispersed in the central nervous system (CNS) and are involved in important physiological processes such as synaptic plasticity and memory formation. NMDA receptors are also implicated in several pathophysiological conditions including Parkinson’s disease, schizophrenia, depression and ischemia. Almost all drugs targeting NMDA receptors are in the discovery or preclinical phase. Additionally, most current drugs and drugs in development globally antagonize NMDA receptor function in the CNS, potentially resulting in adverse side-effects such as dissociative feelings and hallucinations.
Researchers at Emory University have discovered a series of small molecule potentiators to the NMDA receptor. These small molecules have selectivity for NR2C over NR2A/B/D, AMPA, and kainate receptors, reducing the risk of adverse side-effects. NR2C has prominent expression in the cerebellum, thalamus, interneurons, and elsewhere, suggesting selective potentiation could have important effects in the CNS. This small molecule may be useful in treating CNS impairments such as pain, depression, schizophrenia, motor disorders, or addiction.
Early pre-clinical development is underway.
- Zimmerman et al. (2014) Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators. J Med Chem 57: 2334-56
- Khatri et al. (2014) Structural determinants and mechanism of action of a GluN2C-selective NMDA receptors positive allosteric modulator. Molecular Pharmacology 86: 548-560.