Application
GluN2C/2D selective inhibitors that modulate N-methyl-D-aspartic acid receptors (NMDAR) in a subunit-selective manner for treatment of neurological disorders.
Key Benefits
- Specifically targets NMDARs that contain the GluN2C/2D subunit.
- Higher potency and efficacy compared to previously reported GluN2C/2D-selective modulators.
Market Summary
NMDARs have the potential to treat central nervous system (CNS) disorders that involve NMDAR dysfunction, including Alzheimer’s disease, Parkinson’s disease, depression, stroke, schizophrenia, and psychosis. All isoforms of NMDAR subunits are expressed at varying levels throughout the CNS and have unique functional and pharmacological properties implicating different CNS disorders. GluN2C and GluN2D subunits have crucial roles in brain circuits and movements and thus are treated as potential targets for neuropathological diseases. Current market offers several non-specific NMDAR modulators, GluN2B-selective inhibitors like Ifenprodil, and GluN2C/2D specific potentiators/antagonists like CIQ, DQP-1105, QNZ-46, and NAB-14. However, these compounds show lower potency (micromolar range) and which limits their utility in preclinical work. Therefore, a more potent and efficacious drug-like GluN2C or GluN2D subunit-selective NMDAR modulator is needed for treatment of neurological disorders.
Technical Summary
The dihydroquinoline-pyrazoline scaffold (DQP) has been suggested as the noncompetitive and voltage-independent inhibitor of NMDA receptors. Emory University researchers have developed the substitutions on the DQP scaffold that play a crucial role in the activity of inhibition and selectivity at GluN2C/2D subunits over other glutamate receptor subunits. The resulting compounds have improved potency and efficacy compared to earlier DQP, while improving the selectivity for GluN2C/2D subunits over GluN2A/2B. Selected compounds have been identified to show metabolic stability and plasma stability in human, rat, and mouse. These compounds may be effective in treating a wide range of neurological disorders involving movements such as Parkinson’s disease.
Developmental Stage
Compounds have been synthesized.
