Mu opioid receptor (MOR) activation is required for the antidepressant-like effects of both (R,S)-ketamine and the selective NMDAR antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, while FENM had negligible direct MOR activity. Despite these differences, the long-acting MOR antagonist methocinnamox (MCAM) blocked the behavioral effects of both compounds when given before or after stress. The antinociceptive effect of (R,S)-ketamine was more potent and more sensitive to MCAM blockade than that of FENM. These findings suggest that NMDAR antagonists function indirectly through endogenous opioid signaling to produce their effects.
A novel compound, RST-01, a fluoroalkyl derivative of amantadine, shows promise as a treatment for early PTSD in preclinical rat models, producing efficacy without the dissociative side effects or neurotoxic Olney's lesions associated with R,S-ketamine and memantine. In vitro electrophysiological assays measuring IC₅₀ values for human GluN1/GluN2A-D receptors revealed that RST-01 has a more differentiated selectivity profile across the four GluN2 subunits compared to ketamine or memantine. This distinct subunit-specific pharmacological signature offers a mechanistic explanation for the improved safety margins observed, supporting development of safer NMDAR-targeting therapies.