Emory pharmacologists have discovered a new class of potential drugs that might allow them to have their cake and eat it too — with reference to NMDA receptors, important control sites in the brain for learning and memory.

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the cell. Excitotoxicity is thought to be a major mechanism of cell death in stroke and traumatic brain injury.

Usually more sensitivity to NMDA activation and excess calcium go hand in hand. In a new Nature Chemical Biology paper, pharmacologist Stephen Traynelis and colleagues have identified a group of compounds that allow them to separate those two aspects of NMDA signaling.

These compounds appear to selectively decrease how much calcium (as opposed to sodium) flows through the NMDA ion channel. Traynelis says that the discovery opens up pharmacological possibilities for NMDA receptors similar to those for other receptor classes that are prominent drug targets, such as G-protein coupled receptors and acetylcholine receptors. With such receptors, the drugs are called “biased agonists” or “biased modulators” because they shift the balance of how the ion channel responds.

For NMDA receptors, how these newly identified compounds work on a molecular level needs to be explored, and could lead to the long-standing goal of NMDA-based neuroprotection for treatment of stroke/TBI, the authors note. Postdoc Riley Perszyk is first author, with cell biologist Gary Bassell and chemists Dennis Liotta and Lanny Liebeskind as co-authors.

Traynelis discussed this research in his Hodgkin Huxley Katz Prize Lecture to the Physiology 2019 conference in Scotland in December 2019 (the part about the new class of NMDA modulators starts at about 20 minutes).