GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects

Burgdorf, Jeffrey; Zhang, Xiao Lei; Nicholson, Katherine L.; Balster, Robert L.; Leander, J. David; Stanton, Patric K.; Gross, Amanda L.; Kroes, Roger A.; Moskal, Joseph R.

doi:10.1038/npp.2012.246

Cited by 256 publications

(255 citation statements)

References 62 publications

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“…Much of this drug development is focused on discovery of new medications in drug classes populated with known drugs of abuse. Examples include development of anorectics with novel mechanisms of action, biased mu opioid agonists to target selected signaling pathways coupled to mu receptors, selective ligands for GABA A receptor subtypes, and allosteric modulators of NMDA receptors (Mohler, 2012; Burgdorf et al, 2013;DeWire et al, 2013;Fleming et al, 2013). Development of illicit "designer" drugs is also proliferating, and most recently, this has included emergence of novel cathinone derivatives and synthetic cannabinoids (Baumann et al, 2013a;Cottencin et al, 2013;Wiley et al, 2014).…”

Section: B Opportunities For Future Researchmentioning

confidence: 99%

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

2014

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Section: B Opportunities For Future Researchmentioning

confidence: 99%

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

2014

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“…In addition, GLYX-13, a partial agonist of the NMDAR at glycine-binding sites, also has a strong antidepressant effect. If NMDARs are over-activated, GLYX-13 can exert its antidepressant effect mainly by blocking them; if NMDARs are insuffi ciently activated, it can enhance their function and facilitate long-term potentiation [67,68] .…”

Section: The Abnormal Glutamate Receptors Hypothesis and Related New mentioning

confidence: 99%

New hypothesis and treatment targets of depression: an integrated view of key findings

2015

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Major depressive disorder (MDD) is a common and devastating psychiatric disorder characterized by persistent low mood, cognitive disorder, and impaired social function. Despite its complex mechanisms, increasing evidence has identified the involvement of neurotrophic factors, inflammatory cytokines, the hypothalamuspituitary-adrenal axis, and glutamate receptors in the pathophysiology of this illness. The present review synthesizes recent research achievements to defi ne the network between different hypotheses of MDD and to understand which part is most pivotal for its pathogenesis. By integrating MDD-related signal pathways, we highlight brain-derived neurotrophic factor (BDNF) dysfunction and increased apoptosis as the fi nal common cascades, and new therapeutic strategies aiming to enhance BDNF function have been shown to exert a rapid and effective antidepressant action.

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“…Each ligand for a ligand-gated ion channel has a distinct ability to evoke currents (1), and the ligands are classified according to the evoked current level: such as, full agonists, partial agonists, and antagonists. Partial agonists of ligand-gated ion channels reportedly offer clinical advantages over antagonists and full agonists in antidepressant and smoking-cessation treatment (2,3).…”

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confidence: 99%

Conductance of P2X ₄ purinergic receptor is determined by conformational equilibrium in the transmembrane region

Minato

Suzuki

Hara

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ligand-gated ion channels are partially activated by their ligands, resulting in currents lower than the currents evoked by the physiological full agonists. In the case of P2X purinergic receptors, a cationselective pore in the transmembrane region expands upon ATP binding to the extracellular ATP-binding site, and the currents evoked by α,β-methylene ATP are lower than the currents evoked by ATP. However, the mechanism underlying the partial activation of the P2X receptors is unknown although the crystal structures of zebrafish P2X 4 receptor in the apo and ATP-bound states are available. Here, we observed the NMR signals from M339 and M351, which were introduced in the transmembrane region, and the endogenous alanine and methionine residues of the zebrafish P2X 4 purinergic receptor in the apo, ATP-bound, and α,β-methylene ATP-bound states. Our NMR analyses revealed that, in the α,β-methylene ATP-bound state, M339, M351, and the residues that connect the ATP-binding site and the transmembrane region, M325 and A330, exist in conformational equilibrium between closed and open conformations, with slower exchange rates than the chemical shift difference (<100 s −1 ), suggesting that the small population of the open conformation causes the partial activation in this state. Our NMR analyses also revealed that the transmembrane region adopts the open conformation in the state bound to the inhibitor trinitrophenyl-ATP, and thus the antagonism is due to the closure of ion pathways, except for the pore in the transmembrane region: i.e., the lateral cation access in the extracellular region.NMR | membrane proteins | ligand-gated ion channels | insect cell expression system | purinergic receptors I n chemical neurotransmission, various neurotransmitters bind to ligand-gated ion channels expressed in the plasma membrane of postsynaptic cells, such as the NMDA, AMPA, and P2X receptors, leading to changes in membrane potential and the concentration of intracellular ions. Each ligand for a ligand-gated ion channel has a distinct ability to evoke currents (1), and the ligands are classified according to the evoked current level: such as, full agonists, partial agonists, and antagonists. Partial agonists of ligand-gated ion channels reportedly offer clinical advantages over antagonists and full agonists in antidepressant and smoking-cessation treatment (2, 3).Two mechanisms have been proposed for the partial activation of the ligand-gated ion channels: the equilibrium between the open and closed conformations and the distinct conformation of the partial agonist-bound states from the closed and open conformations (4, 5). In the crystal structures of the extracellular region of the AMPA receptor, in which the distances between the two extracellular domains are changed upon agonist binding, the interdomain distances in the partial agonist-bound states correlated with the conductance level, suggesting that the AMPA receptor adopts specific intermediately permeable conformations (4, 6).The P2X receptors are a family of cation channe...

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GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects

Cited by 256 publications

References 62 publications

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

New hypothesis and treatment targets of depression: an integrated view of key findings

Conductance of P2X ₄ purinergic receptor is determined by conformational equilibrium in the transmembrane region

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GLYX-13, a NMDA Receptor Glycine-Site Functional Partial Agonist, Induces Antidepressant-Like Effects Without Ketamine-Like Side Effects

Cited by 256 publications

References 62 publications

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

New hypothesis and treatment targets of depression: an integrated view of key findings

Conductance of P2X 4 purinergic receptor is determined by conformational equilibrium in the transmembrane region

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Conductance of P2X ₄ purinergic receptor is determined by conformational equilibrium in the transmembrane region