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Author Notes:

Stephen F. Traynelis, strayne@emory.edu

Synthesis of the 93 series compounds was completed by Y.A.T., N.S.A., and L.D.H. Oocyte recordings were performed by K.A.N. and L.D.H. S.J.M. performed the triheteromeric recordings. Crystal structure data were provided by H.F. and M.C.R. Spinal nerve ligation and plasma and brain concentration data were collected and analyzed by R.D., S.J.M., and L.J.W. L.D.H performed all tail immersion and locomotor experiments. L.D.H., M.C.R., S.J.M., H.F., L.J.W., R.D., S.F.T., and D.C.L. were involved in experimental design. Data were analyzed by L.D.H., M.C.R., S.J.M., and H.F. All authors were involved in writing the manuscript.

The authors thank Sukhan Kim and James Allen for their excellent technical assistance. They also thank Robert Gereau, PhD, and Shannon Gourley, PhD, for their guidance and feedback on the experimental design and analysis of the work reported here. Receptor binding profiles and Ki determinations were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth, MD, PhD, at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD, United States. We thank the staff at the 17-ID beamlines at the Brookhaven National Laboratory NSLSII, in particular Jean Jakoncic, Alexei Soares, and Vivian Stojanoff, for help with data collection. An atomic coordinate and structure factor for the GluN1b-GluN2B ATDs with EU93-108 is deposited to the Protein Data Bank under the accession code, 8G18.

The authors declare the following competing financial interest(s): S.F.T. is a member of the SAB for Sage Therapeutics, Eumentis Therapeutics, the GRIN2B Foundation, CureGRIN Foundation, a consultant for GRIN Therapeutics, a co-founder of NeurOp, Inc. and AgriThera, and a member of the Board of Directors for NeurOp, Inc. D.C.L. is a member of the Board of Directors for NeurOp, Inc. and co-founder of AgriThera. R.D. is a member of the Board of Directors for NeurOp, Inc. and chair of the Board of Pyrefin, Inc., and a co-founder of NeurOp, Inc. and Pyrefin, Inc.

Subjects:

Keywords:

  • NMDA receptor
  • analgesic tolerance
  • morphine
  • opioid
  • subunit selectivity
  • tail immersion test
  • Animals
  • Morphine
  • Analgesics, Opioid
  • Receptors, N-Methyl-D-Aspartate
  • Rodentia
  • Analgesics
  • Pain
  • Analgesia
  • Dose-Response Relationship, Drug

Novel GluN2B-Selective NMDA Receptor Negative Allosteric Modulator Possesses Intrinsic Analgesic Properties and Enhances Analgesia of Morphine in a Rodent Tail Flick Pain Model

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Journal Title:

ACS Chemical Neuroscience

Volume:

Volume 14, Number 5

Publisher:

, Pages 917-935

Type of Work:

Article | Final Publisher PDF

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 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.

Copyright information:

© 2023 The Authors. Published by American Chemical Society

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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