Nerve cells have a special group of receptors called NMDARs that serve as valves to control the flow of electrical signals in the brain. NMDARs are suspected to play a role in many neurological diseases, including Alzheimer’s, epilepsy, stroke, and Parkinson’s. In a study published today in Nature Communications, researchers created a chemical compound that enabled more precise investigation of NMDAR activity.
The new compound inhibits the activity of certain NMDARs. By inhibiting some NMDARs while letting others function, researchers can now identify the roles that different types of NMDARs play in both healthy and diseased brains.
“There is evidence that GluN2C and GluN2D [a pair of NMDAR subunits] are relevant in the same brain regions where motor functions are affected by Parkinson's disease,” says first author Jue Xiang Wang from CSHL. “Without good inhibitors, we could only speculate on what the 2C and 2D receptors do.”
By inhibiting the activity of GluN2C and GluN2D receptors with higher efficiency and specificity than before, scientists can better study the role that they play in Parkinson’s.
A couple of groups worked together to improve the NMDAR-targeting compound. The CSHL lab specialized in visualizing the physical structure of NMDARs using a technique called X-ray crystallography. Knowing the structure of the receptor was critical for the University of Bristol chemists, who were then able to design a compound called UBP791 to connect specifically with the GluN2C and GluN2D receptors. Studying what makes UBP791 fit particularly well further allowed the scientists to improve the compound, creating its latest version, UBP1700.
The UBP1700 compound is more precise than any of its predecessors and is also more potent. “That’s important because researchers will only need small amounts of the compound to shut down the targeted receptors,” says Wang. “This limits the potential for side-effects that the compound might produce.”
Moving forward, Furukawa’s lab and their Bristol collaborators will be working on further refining the new compound for use in research. For more information, check out their video here.
Image: After seeing exactly how the chemical compound UBP791 fits into a subunit (D1/D2) of an NMDA brain receptor (as visualized above by Furukawa's lab), chemists can now work on designing a version of the compound that fits into that subunit and no others. In this way, they work towards a level of chemical specificity ideal for experiments and drug design. Image courtesy of Furukawa lab/CSHL, 2020.