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J Pharmacol Exp Ther. 2018 Sep;366(3):485-497. doi: 10.1124/jpet.118.249409. Epub 2018 Jul 9.

NYX-2925 Is a Novel N-Methyl-d-Aspartate Receptor Modulator that Induces Rapid and Long-Lasting Analgesia in Rat Models of Neuropathic Pain.

Author information

1
Aptinyx, Inc., Evanston, Illinois (N.G.-H., J.M.P., J.D.A., E.M.C., J.S.B., M.S.B., C.N.C., M.A.K., J.R.M.) and Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (J.S.B., M.S.B., J.R.M.) nayerehhaack@aptinyx.com.
2
Aptinyx, Inc., Evanston, Illinois (N.G.-H., J.M.P., J.D.A., E.M.C., J.S.B., M.S.B., C.N.C., M.A.K., J.R.M.) and Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston, Illinois (J.S.B., M.S.B., J.R.M.).

Abstract

NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide] is a novel N-methyl-d-aspartate (NMDA) receptor modulator that is currently being investigated in phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies demonstrated that NYX-2925 is a member of a novel class of NMDA receptor-specific modulators that affect synaptic plasticity processes associated with learning and memory. Studies here examined NYX-2925 administration in rat peripheral chronic constriction nerve injury (CCI) and streptozotocin-induced diabetic mechanical hypersensitivity. Additionally, NYX-2925 was examined in formalin-induced persistent pain model and the tail flick test of acute nociception. Oral administration of NYX-2925 resulted in rapid and long-lasting analgesia in both of the neuropathic pain models and formalin-induced persistent pain, but was ineffective in the tail flick model. The analgesic effects of NYX-2925 were blocked by the systemic administration of NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid. Microinjection of NYX-2925 into the medial prefrontal cortex of CCI rats resulted in analgesic effects similar to those observed following systemic administration, whereas intrathecal administration of NYX-2925 was ineffective. In CCI animals, NYX-2925 administration reversed deficits seen in a rat model of rough-and-tumble play. Thus, it appears that NYX-2925 may have therapeutic potential for the treatment of neuropathic pain, and the data presented here support the idea that NYX-2925 may act centrally to ameliorate pain and modulate negative affective states associated with chronic neuropathic pain.

PMID:
29986951
DOI:
10.1124/jpet.118.249409

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