Mechanisms of NMDA receptor inhibition by fluoroethylnormemantine - comparison with memantine

Glutamate mediated hyperexcitability related to enhanced activation of N-methyl-D-aspartate receptors (NMDARs) is involved in different pathologies, and one of them is Alzheimer's disease (AD). Despite the development of many NMDAR inhibitors over the last decades, only memantine (MEM) has reached clinical use in AD due to a successful balance of activity, kinetics and mechanisms of action. However, given that MEM has demonstrated only limited symptomatic relief to patients, there is still a need to identify novel NMDAR blockers with suitable properties. In this work, we have studied for the first time the action of recently synthesized MEM derivative fluoroethylnormemantine (FENM) on native rat NMDARs of CA1 hippocampal pyramidal neurons using whole-cell patch clamp method at -80 mV holding voltage. FENM inhibited NMDA receptors more moderately than MEM, but still effectively, with an IC₅₀ value of 6.6 ± 0.6 μM, while MEM had an IC₅₀ of 0.8 ± 0.1 μM. Moreover, FENM inhibited NMDARs via similar mechanisms of action to those of MEM - voltage-dependent channel block with partial trapping and rather fast kinetics - which are important for clinical effectiveness and tolerability. Faster kinetics and moderate activity, still within micromolar range, might alleviate side effects known for MEM. The obtained parameters, as well as the details of mechanisms of action, extend our view of FENM interaction with NMDARs, helping in its development as a new neuroprotective drug.