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

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.

Elucidating the role of keratin 75 in enamel using Krt75tm1Der knock-in mouse model.

Keratin 75 (K75) was recently discovered in ameloblasts and enamel organic matrix. Carriers of A161T substitution in K75 present with the skin condition Pseudofollicullitis barbae. This mutation is also associated with high prevalence of caries and compromised structural and mechanical properties of enamel. Krt75tm1Der knock-in mouse (KI) with deletion of Asn159, located two amino acids away from KRT75A161T, can be a potential model for studying the role of K75 in enamel and the causes of the higher caries susceptibility associated with KRT75A161T mutation. To test the hypotheses that KI enamel is more susceptible to a simulated acid attack (SAA), and has altered structural and mechanical properties, we conducted in vitro SAA experiments, microCT, and microhardness analyses on 1st molars of one-month-old WT and KI mice. KI and WT hemimandibles were subjected to SAA and contralateral hemimandibles were used as controls. Changes in enamel porosity were assessed by immersion of the hemimandibles in rhodamine, followed by fluorescent microscopy analysis. Fluorescence intensity of KI enamel after SSA was significantly higher than in WT, indicating that KI enamel is more susceptible to acid attack. MicroCT analysis of 1st molars revealed that while enamel volumes were not significantly different, enamel mineral density was significantly lower in KI, suggesting a potential defect of enamel maturation. Microhardness tests revealed that in KI enamel is softer than in WT, and potentially less resilient to damages. These results suggest that the KI enamel can be used as a model to study the role of K75 in enamel.