8G18

Heterodimer of the GluN1b-GluN2B NMDA receptor amino-terminal domains bound to allosteric inhibitor 93-108

Summary for 8G18

• Entry DOI: 10.2210/pdb8g18/pdb
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2B, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: nmdar, amino-terminal domain, allosteric inhibitor, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor
• Biological source: Xenopus laevis (African clawed frog); More
• Total number of polymer chains: 4
• Total formula weight: 170548.91

Authors

Regan, M.C.,Furukawa, H. (deposition date: 2023-02-01, release date: 2023-03-01, Last modification date: 2024-10-30)

Primary citation

Harris, L.D.,Regan, M.C.,Myers, S.J.,Nocilla, K.A.,Akins, N.S.,Tahirovic, Y.A.,Wilson, L.J.,Dingledine, R.,Furukawa, H.,Traynelis, S.F.,Liotta, D.C.
Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model.
Acs Chem Neurosci, 14:917-935, 2023

PubMed Abstract: Many cases of accidental death associated with drug overdose are due to chronic opioid use, tolerance, and addiction. Analgesic tolerance is characterized by a decreased response to the analgesic effects of opioids, requiring increasingly higher doses to maintain the desired level of pain relief. Overactivation of GluN2B-containing -methyl-d-Aspartate receptors is thought to play a key role in mechanisms underlying cellular adaptation that takes place in the development of analgesic tolerance. Herein, we describe a novel GluN2B-selective negative allosteric modulator, , that shows high potency and brain penetrance. We describe the structural basis for binding at atomic resolution. This compound possesses intrinsic analgesic properties in the rodent tail immersion test. EU93-108 has an acute and significant anodyne effect, whereby morphine when combined with EU93-108 produces a higher tail flick latency compared to that of morphine alone. These data suggest that engagement of GluN2B as a target has utility in the treatment of pain, and EU93-108 could serve as an appropriate tool compound to interrogate this hypothesis. Future structure-activity relationship work around this scaffold could give rise to compounds that can be co-administered with opioids to diminish the onset of tolerance due to chronic opioid use, thereby modifying their utility.

PubMed: 36779874
DOI: 10.1021/acschemneuro.2c00779

Experimental method

X-RAY DIFFRACTION (2.85 Å)