New drugs for schizophrenia could be in the making thanks to a new class of compounds identified by a research team at Emory University School of Medicine.
The compounds improve signaling in brain molecules, called NMDA receptors, which are believed to function at low levels in schizophrenia.
Led by Stephen Traynelis, PhD, professor of pharmacology, the team sifted through thousands of chemicals and came across CIQ, which proved to selectively boost the actions of certain NMDA receptors without disturbing others.
Currently, schizophrenia is treated with a variety of antipsychotic drugs, which can have various long-term side effects. The idea behind treating schizophrenia via NMDA receptors comes from the observation that when healthy people take the drugs ketamine or phencyclidine (PCP or angel dust), they actually experience the symptoms of schizophrenia for a short period of time, including hallucinations, disorganized thoughts and flattened emotions.
“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.”
Ketamine and phencyclidine both interact with NMDA receptors. Scientists used this knowledge to propose that perhaps a push in the opposite direction chemically — enhancing rather than blocking NMDA receptors.
The hope is that this may help relieve the symptoms of schizophrenia.
NMDA receptors serve as gates that allow electrical charges to surge into neurons when enough glutamate (a neurotransmitter) is present. These receptors are necessary for receiving signals in the brain and are connected with sensory perception, memory and learning.
NMDA receptors are found in different forms. When assembled, they have two parts: one, called NR1, which remains the same throughout the brain, and another that comes in four different variations (NR2A, B, C and D) of differing prominence, depending on the area of the brain under examination.
Currently, only a few drugs can selectively target NMDA receptors that contain different NR2 sub-units. Traynelis and his team were searching for chemicals that would only improve function of the NR2C and NR2D forms. Earlier studies have suggested that enhancement of these sub-units may help in schizophrenia.
“Enhancing NMDA receptor function might compensate for some of the deficits seen in patients with schizophrenia,” he says. “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.”
The discovered compound, called CIQ, makes it easier for NMDA receptor gates to open, although it doesn’t act alone; it still needs glutamate and glycine to bind to the NMDA receptor before it can operate. The researchers also discovered that the parts of NR2C and NR2D NMDA receptors that are CIQ-sensitive are unique from the parts of these receptors known to interact with other known 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 says.
“CIQ is not a drug or clinical candidate,” he adds. “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.”
The results were published Oct. 5, 2010 by the journal Nature Communications.
Source: Emory University