Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits

Abstract

Background Memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been approved for use in Alzheimer’s disease (AD), but increasing 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. Methods We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition (PPI), open field (OF), light dark test (LDT), forced swim test (FST), and cued fear conditioning (FC) in male Wistar rats. Results Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the FST. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued FC training or tone re-exposure. Conclusions These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT4Rs exerts additive effects against stress

“…Our lab and others have shown that K can be administered prior to stress to prevent the onset of stress-induced behavioral despair and decrease learned fear (20)(21)(22)(23)(24)(25). Moreover, we have also demonstrated that fluoroethylnormemantine (FENM), a novel NMDAR antagonist, can also be effective when administered prior to or after stress (26,27). Together, these data strongly suggest that targeting NDMARs can be an effective treatment strategy for stress-related psychiatric disorders.…”

Pharmacological Characterization of [18F]-FNM and Evaluation of NMDA Receptors Activation in a Rat Brain Injury Model

“…The radiolabeled compound ([ 18 F]-FNM) has been developed [ 19 ], and its biodistribution and safety profile have also been studied in rats [ 20 ]. Moreover, FNM recently appeared as a potent neuroprotective drug in Alzheimer’s disease [ 21 ], and its effectiveness has also been demonstrated in rodents for preventing and treating stress-related behaviors [ 22 , 23 ]. It is assumed that this compound binds preferentially extra synaptic NMDARs, mostly involved in excitotoxicity, because of its chemical structure which is close to that of memantine [ 24 , 25 ].…”