GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics

Abstract

N -methyl- D -aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure–function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission. Graphical abstract

Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

“…In this regard, in schizophrenia, NMDARs are believed to be hypoactive; the NMDAR channel blockers PCP and ketamine worsen patients' conditions, and GlyT1 inhibitors were developed in the hope of restoring the NMDAR hypofunction observed in this disorder [116][117][118][119][120][121]. On the contrary, NMDAR hyperfunction has been reported in depression, hypoxic/anoxic conditions, and convulsions [119,[122][123][124][125]. The NMDAR channel blocker ketamine suspends NMDAR overactivity in these conditions [126][127][128], and GlyT1 inhibition exerts antidepressant, neuroprotective, and anticonvulsive effects [122,129,130].…”

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases

“…GluN2B subunit expression was shown to reduce with age which correlates with weakening and decline in cognitive function. Therefore, there is mounting evidence that the GluN2B subunit is an essential subunit that requires attention when considering dementias related to a vast majority of neurodegenerative diseases [125,126]. Moreover, expression of GluN2B subunit reduces with age in animal models, which corresponds with reduced and weak performance in cognition [127,128]; in the frontal cortex of aged humans, there is a decrease in NMDA receptors with pharmacological characteristics associated with the GluN1/GluN2B subtype compared to other subtypes [129]; GluN2B subunit overexpression in the forebrain of transgenic mice has been shown to have significant cognitive benefits [47].…”

Molecular Mechanisms of the Regulation of Liver Cytochrome P450 by Brain NMDA Receptors and via the Neuroendocrine Pathway—A Significance for New Psychotropic Therapies

“…Moreover, the pharmacological impact of drugs acting on glutamate receptors extends to the liver, where these receptors are also expressed [26][27][28]. This issue bears considerable importance, especially in light of the expanding research on novel pharmaceuticals targeting glutamate receptors, such as the selective NMDA receptor antagonists utilized for managing depression [29][30][31][32].…”