NMDARs (N-methyl-D-aspartate receptors) can act as valves for nerve cells and control the flow of electrical signals in the brain. This particular class of receptors is suspected of being present in a variety of neurological diseases, including Alzheimer’s disease, epilepsy, stroke, and Parkinson’s disease. Over the past two decades, many NMDAR inhibitors have been in clinical trials, including the open channel blocker memantine, which has been approved by the FDA for the treatment of Alzheimer’s disease.
Recently, in a research report published in the international journal Nature Communications, scientists from Cold Spring Harbor Laboratory (CSHL) and other institutions have developed a compound that can help more accurately investigate the activity of NMDARs.
Figure 1 Structures of glycine/UBP791 complexed to GluN1–GluN2A (WT) and GluN1–GluN2A-4m LBD
In the article, researchers describe in detail how this novel compound inhibits or blocks the activity of specific NMDARs, by inhibiting some NMDARs and allowing others to function normally. Researchers have identified the key roles that different types of NMDA receptors play in healthy and diseased brains. Researcher Jue Xiang Wang explained that in this study, we revealed the mechanism by which a novel compound called UBP791 targets the NMDAR subunits GluN2C and GluN2D.
There is currently evidence that GluN2C and GluN2D are related in the same brain region, and motor functions in this brain region are affected by diseases such as Parkinson’s. Without good inhibitors, researchers can only speculate on the role of GluN2C and GluN2D receptors.
Today, researchers can inhibit the activity of GluN2C and GluN2D receptors with high efficiency and specificity, and can also analyze their key roles in the pathogenesis of Parkinson’s disease. They improved compounds that targeted NMDARs and used X-ray crystallography to reproduce the physical structure of NMDARs. Elucidating the structure of the receptor was crucial for scientists, and the researchers were then able to design a new compound, UBP791, specifically linked to the GluN2C and GluN2D receptors, much like how to make a key to fit a particular lock. It was continuously improved, and the latest version of the compound named UBP1700 was finally produced.
For a long time, NMDAR has been strongly sought for highly effective subtype-specific reagents for molecular neuroscience research and therapeutic intervention. The current study delineated the critical molecular elements for ligand-binding selectivity for the GluN2C/2D subunits over the GluN2A/2B subunits to be a set of methionine and lysine residues in the ligand-binding pocket of the GluN2C/2D LBD.
Our crystal structure and a series of electrophysiological studies have confirmed that the carboxyethyl group of UBP791 participates in subtype-specific binding and further led to the development of UBP1700 with higher potency and subtype selectivity.
Researcher Wang said that UBP1700 is more accurate and has more potential than previous compound versions. This is important because currently researchers need only a small amount of a compound to turn off the function of a targeted receptor, which limits the potential for side effects from the compound. Later researchers will continue to work together to optimize this new compound to make it more widely used.
References:
- Wang, J.X., Irvine, M.W., Burnell, E.S. et al. Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors. Nat Commun 11, 423 (2020). doi：1038/s41467-020-14321-0