Multispecies translational evaluation of an NMDA receptor modulator reveals analgesic, autonomic-stabilizing, and stress mitigating effects without evidence of abuse liability

Abstract

CNS4 is an agonist concentration-biased NMDAR modulator exhibiting GluN2 subtype-dependent activity. Here we evaluated the translational pharmacology of CNS4 across mice, rats, and client-owned surgical oncology dogs. In mice, CNS4 did not produce conditioned place preference, indicating lack of reward liability. CNS4 produced dose-dependent reductions in locomotor activity without motor impairment on accelerating rotarod testing. CNS4 also maintained body temperature 0.5 to 1 degree Celsius above the vehicle group in mice and dogs, consistent with NMDAR-dependent thermoregulatory activity and contrasting with hypothermic effects reported for NMDAR channel blockers such as ketamine. In fear-conditioning paradigms, CNS4 did not impair fear learning, memory consolidation, or fear expression. CNS4 reduced acute stress-induced sucrose preference, suggesting modulation of stress-responsive neural circuits. In a rat spinal nerve ligation model of neuropathic pain, both single-dose and three-day repeated CNS4 administration significantly reversed mechanical, pressure, and thermal hypersensitivity, supporting analgesic efficacy with no apparent evidence of rapid tolerance development. In client-owned surgical oncology dogs undergoing standard veterinary procedures, preliminary findings from 14 dogs (8 CNS4-treated, 6 vehicle-treated) demonstrated stable intraoperative mean arterial pressure and heart rate. Postoperatively, CNS4-treated dogs exhibited normal physiological recovery, with respiratory rate, heart rate, and body temperature returning toward the normal canine range, and required approximately 8% less propofol for anesthetic induction. Collectively, these findings support CNS4 as a novel NMDAR modulator with thermoregulatory, anti-agitative, analgesic, and autonomic-stabilizing properties without evidence of abuse liability, supporting continued translational development for neuropathic pain and possibly neuropsychiatric disorders.