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Biological Basis of Behavior
Published in Mohamed Ahmed Abd El-Hay, Understanding Psychology for Medicine and Nursing, 2019
Glycine is an inhibitory neurotransmitter found primarily in the spinal cord. Glycine is a nonessential amino acid that is synthesized in the brain from L-serine by serine hydroxymethyltransferase. It works on its own and as a regulator of the excitatory neurotransmitter glutamate. Termination of the synaptic action of glycine is through reuptake into the presynaptic terminal by the glycine transporter II (GlyT2), which is quite distinct from GlyT1 that is expressed in astrocytes and modulates the NMDA receptor function.
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
After its release into the synaptic cleft, glycine is primarily inactivated by reuptake into the terminal of the releasing neuron or by uptake into glial cells. Glycine reuptake is carried out by a glycine transporter in the membrane. The Na+ and Cl− electrochemical gradients assist in the movement of glycine against its concentration gradient.161 Two glycine membrane transporters have been identified by molecular cloning: GLYT-1 and GLYT-2. It appears that GLYT-1 is found in both neurons and glial cells, and GLYT-2 is localized to neurons. Both transporters are expressed in the hindbrain whereas GLYT-1 can also be found in forebrain areas even though there are few, if any, glycinergic terminals. Because glycine also functions as a coagonist with glutamate at NMDA receptors (see text on glycine receptors and EAA), there is speculation that the GLYT-1 transporter might regulate glutamate receptor function in forebrain areas.161 Selective inhibitors of the glycine transporter are not yet available but could become useful drugs in the future for the treatment of pain or epilepsy (see the following). It has been suggested that GLYT-1 is the primary glial transporter, and GLYT-2 is the primary neuronal transporter, but this remains somewhat controversial.1
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Khalid A. Agha, Nader E. Abo-Dya, Abdul Rashid Issahaku, Clement Agoni, Mahmoud E. S. Soliman, Eatedal H. Abdel-Aal, Zakaria K. Abdel-Samii, Tarek S. Ibrahim
Full activation of NMDARs requires agonist binding at two glycine and two glutamates on the tetrameric complex. Several experimental studies showed that the glycine site was likely to be fully occupied in vivo either by glycine itself or by D-serine.16 On the other hand, it was found that at some locations in the central nervous system, the glycine site is not fully saturated by glycine due to the activity of high-affinity glycine transporters (GlyT-1).17 The requirement for occupation of the glycine site has been derived from a number of observations that blocking glycine site in NMDAR exacerbates psychotic symptoms in schizophrenic individuals and impairs cognitive performance in healthy individuals.18 As a result of this, glycine binding site has attracted attention of many scientists as a potential target for safely elevating the activity of NMDARs.19 A number of potential strategies for enhancing NMDAR function and hence improving cognition via the glycine site had developed like administration of glycine but this strategy is limited by the high activity of GlyT-1, so effort is moved to develop GlyT-1 inhibitors like Pfizer sarcosine analogue CP-802079 (Figure 2). Limitation of this approach is activation of inhibitory glycine receptors.17,20 Another promising approach involves exogenous administration of partial agonists like Sunifiram.21,22
Emerging drugs for the treatment of postsurgical pain
Published in Expert Opinion on Emerging Drugs, 2021
Esra Kutlu Yalcin, Jorge Araujo-Duran, Alparslan Turan
Understanding the different molecular pathways associated with pain has led to the discovery of new potential targets. For instance, the glycinergic pathway localized in specific brain regions and spinal cord has been shown to play an important role in the regulation of pain signal transduction, specifically through the Glycine transporter (GlyT) 1, which is present in glial cells, and GlyT2, which is located in neurons [38]. The transporters modulate glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons, modifying pain signal transmission in the spinal cord [38]. Previous preclinical studies demonstrated that blocking GlyT1 and GlyT2 produced a profound anti-allodynic effect in neuropathic pain models, mainly through the stimulation of the glycine receptor α3 [38]. This suggested the GlyTs as targets to develop medications for neuropathic and postoperative pain. Another pathway involves 5HT2A, a subtype of the 5HT2 serotonin receptor widely expressed in peripheral sensory neurons and responds to serotonin released during inflammation or nociceptive stimulation. It is also expressed in the midbrain neuron terminations and is involved in the amplification of pain signals in the spinal dorsal horn [39]. Different preclinical pain models led to the finding of the synergistic action between GlyT2 and 5HT2A inhibition as a potential drug to treat postoperative pain.
Emerging therapeutic targets for schizophrenia: a framework for novel treatment strategies for psychosis
Published in Expert Opinion on Therapeutic Targets, 2021
Susan F. Sonnenschein, A Grace
Numerous glutamate-targeting compounds have been evaluated in clinical trials. NMDA receptor co-agonists, including D-cycloserine, D-serine, and glycine, were among the earliest studied in an effort to enhance NMDA-mediated interneuron function [90], thereby increasing inhibition of pyramidal neurons. Despite initial promise in clinical trials, none of these compounds passed phase 2 or phase 3 clinical trials as either a monotherapy or adjunct to current treatments [91,92]. Selective glycine transporter 1 (GlyT1) inhibitors, such as sarcosine and biopertin have also been tested as an alternative method to increase the availability of glycine at NMDA receptors [93]. Sarcosine has demonstrated success in clinical trials as an adjunct treatment in early clinical trials in improving positive, negative, and cognitive symptoms [94,95] with some evidence for greater efficacy than NMDA receptor agonists [96]. However, not all trials have shown significant results with GlyT1 inhibitors, such as when added to clozapine or tested as a monotherapy [97–99]. D-amino acid oxidase (DAAO) inhibition with compounds such as sodium benzoate has also recently been explored as a method of enhancing NMDA receptor activation by blocking D-amino acid metabolism. Sodium benzoate has produced promising results as an adjunctive therapy in early clinical trials [100–102]. Larger clinical trials are needed to better assess the potential benefits of NMDA receptor-targeting drugs.