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. 2023 Mar 1;14(5):917-935. doi: 10.1021/acschemneuro.2c00779. Epub 2023 Feb 13.


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 N-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, EU93-108, 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.

Keywords: NMDA receptor; analgesic tolerance; morphine; opioid; subunit selectivity; tail immersion test.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesia*
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use
  • Animals
  • Dose-Response Relationship, Drug
  • Morphine*
  • Pain / drug therapy
  • Pain / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Rodentia / metabolism


  • Morphine
  • Analgesics, Opioid
  • Receptors, N-Methyl-D-Aspartate
  • Analgesics