N-methyl-D-aspartate receptors (NMDARs) are crucial ionotropic receptors for the excitatory neurotransmitter glutamate, playing a key role in Ca²⁺ ion permeability and excitatory neurotransmission in the brain. Composed of several subunits, including GluN1, GluN2, and GluN3, NMDARs are widely distributed in the brain and regulate various neurotransmission systems, essential for functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. This review details the structure, composition, and localization of NMDARs, their role and regulation at glutamatergic synapses, and their impact on cognitive processes and neurodegenerative diseases (Alzheimer’s, Huntington’s, and Parkinson’s disease). The pharmacology of different NMDAR antagonists and their therapeutic potentialities are discussed, with a focus on fluoroethylnormemantine (FENM), an investigational drug showing promising neuroprotective and anxiolytic properties in Alzheimer’s and post-traumatic stress disorder (PTSD) models. FENM has been shown to alleviate amyloid toxicity and improve cognitive deficits in Alzheimer’s preclinical models, and to reduce fear behavior and enhance extinction learning in PTSD models. The review highlights the potential of FENM as a novel therapeutic agent for neurodegenerative and neuropsychiatric disorders.N-methyl-D-aspartate receptors (NMDARs) are crucial ionotropic receptors for the excitatory neurotransmitter glutamate, playing a key role in Ca²⁺ ion permeability and excitatory neurotransmission in the brain. Composed of several subunits, including GluN1, GluN2, and GluN3, NMDARs are widely distributed in the brain and regulate various neurotransmission systems, essential for functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. This review details the structure, composition, and localization of NMDARs, their role and regulation at glutamatergic synapses, and their impact on cognitive processes and neurodegenerative diseases (Alzheimer’s, Huntington’s, and Parkinson’s disease). The pharmacology of different NMDAR antagonists and their therapeutic potentialities are discussed, with a focus on fluoroethylnormemantine (FENM), an investigational drug showing promising neuroprotective and anxiolytic properties in Alzheimer’s and post-traumatic stress disorder (PTSD) models. FENM has been shown to alleviate amyloid toxicity and improve cognitive deficits in Alzheimer’s preclinical models, and to reduce fear behavior and enhance extinction learning in PTSD models. The review highlights the potential of FENM as a novel therapeutic agent for neurodegenerative and neuropsychiatric disorders.