NMDAR agents for the treatment of various neurological diseases.
More than a billion people worldwide suffer from neurological disorders such as Alzheimer's (AD), Parkinson's (PD), multiple sclerosis, epilepsy, stroke, or autism. Although significant scientific advances have been made in determining the pathogenesis of these diseases, there remains a critical unmet medical need as limited efficacious therapies are available. N-methyl-D-aspartate receptors (NMDARs) are glutamate and ion channel proteins in various nerve cells and play a pivotal role in synaptic transmission and synaptic plasticity for memory function and learning. In many neurodegenerative diseases, synaptic dysfunction resulting from the overactivation of NMDARs is believed to be a potential therapeutic target for treatment. As a result, there has been a push to develop pharmacologic agents that alleviate NMDAR dysfunction to treat neurological disorders. For example, drugs such as Memantine have been approved to treat moderate to severe Alzheimer's disease; however, their clinical efficacy is questionable. Due to the limited efficacy of NMDAR agents, there is an unmet need to develop new NMDAR modulators to treat neurological disorders.
Researchers have proposed a small molecule compound via the positive allosteric modulation of GluN1/GluN3A N-Methyl-D-Aspartate Receptors as a novel treatment for neurological diseases. Numerous neurological disorders and pathological conditions have displayed abnormal expressions and altered N-Methyl-D-aspartate receptor (NMDAR) function. Modulation of the GluN3A subunit of NMDAR receptors has been suggested to be neuroprotective, influence synaptic develop, plasticity, and place aversion conditioning. Researchers found that the compound EU1180-490 served as a potent and selective potentiator of the GluN1/GluN3 NMDARs, furthermore the compound has Lipinski drug-like properties such as low molecular weight/cLogP and high-water solubility.