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

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 -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.

NYX‐2925 induces metabotropic N‐methyl‐d‐aspartate receptor (NMDAR) signaling that enhances synaptic NMDAR and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor

“…and Khan et al ) via increasing synaptic GluN2B as shown both in vitro (Fig. ) and in vivo (Khan et al ; Ghoreishi‐Haack et al ; Supporting Information). This pharmacokinetic‐based plasticity model (Fig.…”

“…). This same dose also facilitated novel object recognition and positive emotional learning (Khan et al ) as well as reduced neuropathic pain in rats (Ghoreishi‐Haack et al ). Thus, mid‐nanomolar NYX‐2925 concentrations facilitate cognition and LTP.…”

NYX‐2925, A Novel N‐methyl‐D‐aspartate Receptor Modulator: A First‐in‐Human, Randomized, Double‐blind Study of Safety and Pharmacokinetics in Adults

“…NYX‐2925 has been studied in several animal models of neuropathic pain, including neuropathic pain induced by sciatic nerve ligation and painful diabetic neuropathy‐induced pain with streptozotocin. In the Bennett chronic constriction injury model of neuropathic pain, rats given a single dose of NYX‐2925 at 1–2 weeks post‐sciatic nerve ligation demonstrated analgesia at 1 hour, 24 hours, and 1 week postdrug administration . Similar rapid (1 hour) and long‐lasting (1 week) analgesia was observed in the rat model of streptozotocin‐induced painful diabetic neuropathy .…”

“…In the Bennett chronic constriction injury model of neuropathic pain, rats given a single dose of NYX‐2925 at 1–2 weeks post‐sciatic nerve ligation demonstrated analgesia at 1 hour, 24 hours, and 1 week postdrug administration . Similar rapid (1 hour) and long‐lasting (1 week) analgesia was observed in the rat model of streptozotocin‐induced painful diabetic neuropathy . NYX‐2925 modulates NMDARs in a highly specific and selective manner to enhance synaptic plasticity, which is a probable mechanism for the long‐duration effects seen in these pain models.…”

“…Half‐life was ~4 hours after single‐dose administration and trended higher on day 7 vs. day 1 in the MAD phase. However, although single doses in preclinical studies have shown efficacy in models of chronic pain, once‐daily doses were also able to convey and maintain analgesia, with long‐lasting (1 week) effects, far exceeding that of NYX‐2925 half‐life . Therefore, a once‐daily dosing regimen is being evaluated in the phase II studies.…”