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

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.

The NMDAR modulator NYX-2925 alleviates neuropathic pain via a Src-dependent mechanism in the mPFC.

Previous studies have shown that oral administration of the NMDAR modulator NYX-2925 alleviates pain in several animal models of neuropathic pain and this appears to be through mPFC, but not spinal, mediated mechanisms. While much is known about the impact of neuropathic pain on NMDAR-mediated signaling in the spinal cord, limited studies have focused on the brain. In the current study, we assess signaling changes associated with NMDAR-mediated plasticity in the mPFC and the impact of NYX-2925 administration on the normalization of these signaling changes. We found a decrease in activated Src levels in the mPFC of animals with chronic constriction injury (CCI) of the sciatic nerve. While Src mediated activation of NMDARs was also decreased in CCI animals, the main NMDAR phosphorylation site of CAMKII was not affected. This is in opposition to what has been found in the spinal cord, where both Src and CAMKII activation are increased. Oral administration of NYX-2925 restored levels of activated Src and Src phosphorylation sites on GluN2A and GluN2B in the mPFC, with no effect on activated CAMKII levels. The analgesic effect of NYX-2925 appears dependent on this restoration of Src activation in the mPFC, as co-administering Src activation inhibitors prevented the NYX-2925 analgesic effect. Overall, these data suggest that NMDAR-mediated signaling plays a key role in neuropathic pain, albeit in different directions in the spinal cord vs. the mPFC. Furthermore, the analgesic effect of NYX-2925 appears to involve a restoration of NMDAR-mediated signaling in the mPFC.