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

Nayereh Ghoreishi-Haack,Jeffrey S Burgdorf,M Amin Khan,Jessica M Priebe,M Scott Bowers,Cassia N Cearley,Elizabeth M Colechio,Jacqueline D Aguado,Joseph R Moskal

doi:10.1124/jpet.118.249409

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.

Highlights

Neuropathic pain is a chronic, debilitating condition arising from insults to the central and peripheral nerves (Gilron et al, 2015)
Because chronic pain is a multifaceted disease that cannot be adequately captured via a single model, the analgesic effect of NYX-2925 was tested in constriction nerve injury (CCI)- and diabetes-induced neuropathic pain models
Because neuropathic pain involves both sensory and affective components, the effects of NYX-2925 on emitted ultrasonic vocalization (USV) were assessed in the heterospecific rough-and-tumble-play model in animals with CCI-induced neuropathic pain

Summary

Introduction

Neuropathic pain is a chronic, debilitating condition arising from insults to the central and peripheral nerves (Gilron et al, 2015). There are multiple compounds marketed for the treatment of neuropathic pain, there is still a high unmet medical need. The impaired cognitive and emotional states that are often comorbid with chronic pain remain largely unaddressed with current. Portions of this work was previously presented: 2016: American Pain Society, Austin TX; International Association for the Study of Pain, Yokohama, JP; Society for Neuroscience, San Diego, CA 2017: American Pain Society Pittsburgh, PA; Society for Neuroscience, Washington, DC 2018: American Pain Society, Anaheim, CA. There is a growing need for new therapeutics for the treatment of neuropathic pain

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