Glycine acts as a neurotransmitter at two distinct receptor systems. In the spinal cord and certain non-cerebral brain regions, glycine acts much like GABA (γ-amino-n-butyric acid) in causing the opening of an inhibitory Cl− channel. This activity is mediated by the “strychnine-sensitive” glycine receptor. Glycine also acts as a co-agonist at the NMDA (N-methyl-D-aspartate) glutamate receptor that is localized in the cognitive centers of the brain, including the cortex, hippocampus, and basal ganglia. This receptor has received considerable attention from the pharmaceutical industry since there is compelling evidence that it plays a critical role in learning and cognition. Furthermore, excessive stimulation of the NMDA receptor appears to be responsible for much of the neuronal damage that occurs after stroke-injury and brain trauma. Hence, there are ongoing research efforts to develop both agonists (for increased cognition) and antagonists (for treatment of stroke) to the NMDA receptor.
Recent data suggest that agonists and antagonists to the glutamate site of the NMDA receptor can cause relatively severe side-effects. For example, NMDA antagonists have been shown to cause agitation, hallucinations, and paranoia in stroke patients. Agonists to the glutamate binding site on NMDA receptors have the potential of causing excessive calcium influx and excitotoxic cell damage. In contrast, the glycine site on the NMDA receptor appears to play a modulatory role, and therefore compounds interacting with this site do not appear to evoke such severe side-effects.