Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator

Abstract

3.AbstractNMDA receptor (NMDAR) channel blockers, which produce analgesic and anti-depressant effects, preferentially block the GluN2D subtype of NMDAR at lower doses. Based on the knowledge of GluN2 subunit physiology, we hypothesized that compounds that concurrently modulate GluN2A and GluN2D subtypes of NMDARs to opposite directions can be useful analgesic and stress-mitigating agents. In this translational study, we explored in vivo activities of a recently discovered glutamate concentration-dependent NMDAR modulator (CNS4). Results from the pharmacokinetic study indicate that CNS4 reaches maximum plasma and brain concentration as quickly as 0.25 hours after intraperitoneal injection, and about 6% of the plasma concentration reaches brain tissue (54.5 vs 3.3 µg/ml). In preliminary in vivo studies, CNS4, a non-opioid compound, increased mice escape latency in a hotplate assay by 2.18-fold compared to saline and 1.78-fold compared to the positive control, meloxicam. Furthermore, in a fear conditioning (FC) experiment, CNS4 improved fear memory [decrease in freezing latency (11.78 vs 4.42s, p=0.0010)] and subsequent fear extinction [increase in freezing latency (3.56 vs 15.08s, p=0.049)] in male mice. CNS4 caused no changes in locomotion in 8 out of 9 parameters studied. About fifty hours after FC training, CNS4 increased water (5-fold) and sucrose intake (4.5-fold) in male mice. These results indicate that the glutamate concentration-biased modulatory effect of CNS4 could produce analgesia and stress-mitigating effects. Further studies in this direction will help develop clinically useful drugs for pain associated with stressful conditions.4.SignificanceNMDA-subtype glutamate receptors are an attractive target for chronic pain and PTSD treatments as they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and male sex-specific fear memory formation and fear extinction characteristics of a novel glutamate concentration-biased NMDA receptor modulator, CNS4.5.Visual AbstractVisual Abstract