Elevation of extracellular synaptic glycine concentration by blockade of GlyT1 has been hypothesized to potentiate NMDA receptor function in vivo and to represent a rational approach for the treatment of schizophrenia and cognitive disorders.

Org 24598
ASP 2535
Yoda 1
SSR 504734


An overview of GlyT1

The glycine transporter (GlyT1) is a member of the sodium-potassium-dependent transporter family, which mediates the transfer of glycine from the extracellular cell and regulates the concentration of glycine in the synaptic gap. There are two subtypes of glycine, including transporter-1 (GlyT1) and glycine transporter-2 (GlyT2), of which GlyT1 is distributed in the the spinal cord, brainstem, cerebellum, olfactory bulb and other regions of central nervous system.

Activation of GlyT1

Bitopertin is an effective selective inhibitor of GlyT1, and EC50 is 30 nM. N-methyl D-aspartate (NMDA) receptor is a key cause of signs and symptoms in many schizophrenia. The hyperactivity of NMDA receptor can alleviate the dysfunction of the conduction of receptor signal and is expected to be used for schizophrenia treatment. The allosteric glycine site of target NMDA receptor can enhance the function of NMDA receptor and restore the delivery of normal glutamate. This effect can be achieved through the glycine agonist and by inhibiting GlyT1 and preventing the removal of glycine during the synapse. Bitopertin selectively suppresses GlyT1, thereby increasing the number of glycine (NMDA receptor synergistic agonist) in the synapse and ultimately enhancing NMDA signaling.

GlyT1 and diseases

Studies have shown that glycine transporters can mediate the transfer of glycine from the extracellular cell, while the different concentrations of glycine have the function of activating NMDA receptor and glycine receptor in synaptic interstitial. The former increases the excitability of neurons, and the latter decreases its excitability and increases the degree of inhibition of the nervous system. Therefore, the suppressant glycine receptor and excitatory glutamate receptors play a role in regulating synaptic function and nerve transfer in the brain and spinal cord level, and may affect the opioid-induced hyperalgesia (OIH), while glycine concentration is regulated by glycine transporter in the synaptic interstitial, especially GlyT1. In the suppressant synapses, the GlyT1 can shorten the postsynaptic reaction time, and in the excitatory synapses, the GlyT1 can prevent the NMDA receptor from saturating. Therefore, it is an effective method to develop new antipsychotic drugs to block the uptake of glycine from GlyT1 in the synaptic interstitial to enhance the function of neurotransmitter from NMDA receptor.