Glycine is released from the presynaptic terminal as a classic inhibitory neurotransmitter, which hyperpolarizes the postsynaptic membrane by activating glycine receptors (GlyRs) with essential anion channels. In addition, glycine also modulates the activity of excitatory NMDA (N-methyl-D-aspartate) selective glutamate receptors at excitatory synapses by acting as a secondary agonist.
Introduction to GlyRs
Glycine was first identified as an inhibitory neurotransmitter in the spinal cord in the 1960s. In the human central nervous system (CNS), GlyRs are distributed in the human forebrain, brainstem and cervical spinal cord. Glycine binds to the glycine B (NMDA receptor coupled and insensitive to strychnine) regulatory site on the NMDA receptor subunit 1 (NR1) with an affinity of 0.1-3.0 μm, and regulates excitatory transmission. There are two glycine transporters, glycine transporter 1 (GlyT1) and 2 (GlyT2). GlyT1 is expressed in the medulla oblongata including the thalamus and hypothalamus. In the forebrain area, GlyT1 is found in the presynaptic and postsynaptic densities of glial cells and asymmetric glutamatergic synapses, which co-localize with NMDA receptors. This co-localization provides support for the hypothesis that glycine plays a key role in NMDA-mediated neurotransmission in the forebrain.
Function of Glycine reuptake inhibitor (GRI) in Schizophrenia
In rat models, it has been shown that increasing the function of NMDA receptors can reduce the phenotype of schizophrenia positive and negative symptoms. Research models for the under-functioning NMDA receptors in schizophrenia include supplementing antipsychotics with ligands and inhibiting ligand reuptake. GRI is a drug that inhibits the neurotransmitter glycine reuptake by blocking one or more GlyTs. Currently, GRIs have been used to indirectly increase glycine in the synaptic cleft. Preliminary trials of GlyT1 inhibitors (sarcosine (N-methylglycine) derivative GRI) were conducted using a sarcosine derivative, and the efficacy has been demonstrated in preclinical data from a rat model. When sarcosine or its derivatives were added to chronic schizophrenia, the changes in the total score of the positive and negative syndrome score (PANSS) were measured, and the results were encouraging.
GRIs Development Services at Creative Biolabs
As mentioned above, glycine regulatory sites on NMDA receptors are one of the attractive targets for the development of potential therapeutic drugs for schizophrenia. One way to improve NMDA receptor function is to pharmacologically increase synaptic glycine levels by GlyT-1 inhibitors.
Scientists at Creative Biolabs are committed to understanding the role of GlyT-1 in the treatment of schizophrenia, hoping to provide a new perspective for the treatment of this disease. With the deepening of psychiatric research and understanding of schizophrenia, further trials are needed to meet the unmet needs of treating schizophrenia. On this basis, GRIs are still promising therapies, so we propose drug development services for GRIs. If you are interested in our service, please contact us.
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