Fluoroethylnormemantine, a novel NMDA receptor antagonist for the prevention and treatment of stress-induced maladaptive behavior
Briana K. Chen, Victor M. Luna, Margaret E. Shannon, Holly C. Hunsberger, Alessia Mastrodonato, Michelle Stackmann, Josephine C. McGowan, Gilles Rubinstenn, Christine A. Denny
Abstract: Major depressive disorder is a common, recurrent illness. Recent studies have implicated the NMDA receptor in the pathophysiology of major depressive disorder. (R,S)-ketamine, an NMDA receptor antagonist, is an effective antidepressant but has numerous side effects. Here, we characterized a novel NMDA receptor antagonist, fluoroethylnormemantine (FENM), to determine its effectiveness as a prophylactic and/or antidepressant against stress-induced maladaptive behavior. Saline, memantine (10 mg/kg), (R,S)-ketamine (30 mg/kg), or FENM (10, 20, or 30 mg/kg) was administered before or after contextual fear conditioning in 129S6/SvEv mice. Drug efficacy was assayed using various behavioral tests. Protein expression in the hippocampus was quantified with immunohistochemistry or Western blotting. In vitro radioligand binding was used to assay drug binding affinity. Patch clamp electrophysiology was used to determine the effect of drug administration on glutamatergic activity in ventral hippocampal cornu ammonis 3 (vCA3) 1 week after injection. Given after stress, FENM decreased behavioral despair and reduced perseverative behavior. When administered after re-exposure, FENM facilitated extinction learning. As a prophylactic, FENM attenuated learned fear and decreased stress-induced behavioral despair. FENM was behaviorally effective in both male and female mice. (R,S)-ketamine, but not FENM, increased expression of c-fos in vCA3. Both (R,S)-ketamine and FENM attenuated large-amplitude AMPA receptor–mediated bursts in vCA3, indicating a common neurobiological mechanism for further study. Our results indicate that FENM is a novel drug that is efficacious when administered at various times before or after stress. Future work will further characterize FENM’s mechanism of action with the goal of clinical development.
Fluoroethylnormemantine, a novel derivative of memantine, facilitates extinction learning without sensorimotor deficits
Briana K. Chen, Gwenaelle Le Pen, Adam Eckmier, Gilles Rubinstenn, Therese M. Jay, Christine A. Denny
Abstract: Memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been approved for use in Alzheimer’s disease, but an increasing number of studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition, open field, light dark test, forced swim test, and cued fear conditioning in male Wistar rats. Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the forced swim test. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued fear conditioning training or tone re-exposure. These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.
Patents
Compositions and methods for the prevention of stress-induced fear, depressive-like and anxiety-like behavior, PCT/US21/26184
Prophylactic efficacy of FENM against stress-induced depression, US62/848,406
Prophylactic efficacy of FENM against stress-induced depression, US62/861,765