Schizophrenia Patients to Thank PCP and Angel Dust Users?

With a belief that NMDA receptors function at low levels in people with schizophrenia, Emory University School of Medicine researchers have identified a class of compounds that enhance signaling by NMDA receptors. Thought to selectively enhance the function of specific NMDA receptors while not affecting others, the compound, CIQ, was discovered after the team, Led by Stephen Traynelis, PhD, professor of pharmacology, sifted through thousands of chemicals.

The idea to treat schizophrenia via NMDA receptors developed out of knowledge that consumption of PCP or angel dust—both of which interfere with NMDA receptors— causes healthy people to temporarily experience schizophrenia symptoms, like hallucinations, disorganize thoughts, and flattened emotions, according to the authors, who published their work in Nature Communications. Theoretically, enhancing rather than blocking NMDA could help relieve symptoms of schizophrenia.

"There is room for improvement in therapeutic treatment of schizophrenia," Traynelis says. "Exploration of alternative targets, such as the NMDA receptor, could potentially lead to expanded treatment options and improved outcomes for patients with schizophrenia."

NMDA receptors—which act as gates that allow electrical charges to flow into neurons when glutamate is present and play a key role in receiving brain signals connected with sensory perception, learning, and memory—come in several forms and have two parts when assembled. One part, NR1, remains the same throughout the brain, whereas the other, NR2, comes in varieties A, B, C, and D and with varying prominence depending on the brain region. The current research was looking specifically for chemicals that enhance the function of NR2C and D, as previous studies suggest that enhancement of the two could help in treating schizophrenia.

"Enhancing NMDA receptor function might compensate for some of the deficits seen in patients with schizophrenia," said Traynelis. "Because NMDA receptors play a number of important roles in the brain, we sought to target only those subunits that have been suggested to potentially improve symptoms in patients with schizophrenia."

When the research team saw that CIQ allows NMDA receptor gates to more easily open, they knew they’d found their compound. Acting with the help of glutamate and glycine, which allow it to bind to NMDA receptors, the effects of CIQ were felt with more sensitivity in parts of NR2C and D that differ from regions of NMDA receptors that are know to interact with other drugs.

"CIQ appears to act at a new, physically distinct site on the receptor that could offer an opportunity to manipulate receptor function in a variety of ways," Traynelis added. "CIQ is not a drug or clinical candidate. Rather, it marks the beginning of a process that involves fine tuning the structure to build potent, selective, and well-tolerated compounds. Later, these can be evaluated in clinical trials to determine whether the strategy of enhancing NMDA receptor signaling does indeed improve the lives of patients with schizophrenia. In addition, compounds emerging from this optimization process could become useful tools for dissecting NMDA receptor contributions to cognition, learning, memory, as well as other diseases.”