Targeting Glycine Modulation of NMDA Glutamate Receptors

Adjunct Professor of Psychiatry, University of California, San Diego

New Trend in Psychopharmacology

Currently, a major hypothesis for the pathophysiology of schizophrenia proposes that numerous risk factors converge on the N-methyl-D-aspartate (NMDA) receptor for the neurotransmitter glutamate, resulting in neurodevelopmental abnormalities at glutamate synapses and hypofunction of NMDA receptors. Novel treatments are now in development that can theoretically boost the function of NMDA receptors by enhancing actions at the glycine co-transmitter site of this receptor complex.

New Treatment Strategies for Schizophrenia 

Pharmacologic approaches that involve direct enhancement of glutamate risk excitotoxicity from excessive glutamate action. Thus, a potentially safer way to enhance glutamate is to exploit the fact that NMDA glutamate receptors also require glycine actions at a co-transmitter site. NMDA receptors are an interesting type of “coincidence detector” that can open to allow calcium into the neuron to trigger postsynaptic actions from glutamate neurotransmission only when three things occur at the same time: glutamate occupies its binding site on the NMDA receptor, glycine or D-serine binds to its site on the NMDA receptor, and depolarization occurs. 

Targeting Glycine Modulation of NMDA Receptors

Glycine Agonists

Agonists at the glycine site of NMDA receptors include the naturally occurring amino acids glycine and D-serine. An analogue of D-serine, called D-cycloserine is also active at the glycine co-agonist site of NMDA receptors. All of these agents have been tested in schizophrenia with evidence that they can reduce negative and/or cognitive symptoms. Further testing of these naturally occurring agents is in progress and synthetic agonists with greater potency are in discovery.

GLY-T₁ Inhibitors

The GLY-T₁ reuptake pump is the major route of inactivation of synaptic glycine, so it is logical to explore the ability of GLY-T₁ inhibitors to enhance synaptic actions of glycine, and, thus, of NMDA receptors. Several GLY-T₁ inhibitors are now in testing, including the natural agent N-methyl-glycine, also known as sarcosine, as well as drugs in preclinical testing, such as SSR 504734, SSR 241586, JNJ17305600, and Org 25935. GLY-T₁ inhibitors are analogous to drugs that inhibit reuptake of other neurotransmitters, such as the serotonin selective reuptake inhibitors and their actions at the serotonin transporter. When GLY-T₁ pumps are blocked by a GLY-T₁ inhibitor, this increases the synaptic availablility of glycine, and thus enhances NMDA neurotransmission. Sarcosine has been shown to improve negative, cognitive, and depressive symptoms, including symptoms such as alogia and blunted affect in schizophrenia. The hope is that GLY-T₁ inhibitors with greater potency, such as those in preclinical testing mentioned above, will be even more effective.

Disclosure: Dr. Stahl is a consultant to, is on the speaker’s bureaus of, or receives grant/research support from Acadia, Amylin, AstraZeneca, Biolaunch, Biovail, Bristol-Myers Squibb, Boehringer-Ingelheim, Cephalon, CSC Pharmaceuticals, Cyberonics, Cypress, Eli Lilly, Epix, Forest, GlaxoSmithKline, Janssen, Neurocrine, Neuromolecular, Neuronetics, NovaDel, Novartis, Organon, Otsuka, Pfizer, Pierre Fabre, Sanofi, ScheringPlough, Sepracor, Solvay, Shire, Somaxon, Tetragenix, and Wyeth.