Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration.

Area of Science:

• Neuroscience
• Pharmacology
• Medicinal Chemistry

Background:

• N-methyl-D-aspartate (NMDA) receptors are key for brain function, including learning and memory.
• Selective modulation of NMDA receptor subtypes, like GluN2A, is difficult but important for treating neurological disorders.
• Previous compounds (MPX-004, MPX-007) were selective for GluN2A but had poor physical properties for in vivo use.

Purpose of the Study:

• To optimize the MPX-004/MPX-007 scaffold for improved drug-like properties.
• To develop novel, potent, and selective GluN2A receptor modulators.
• To create new tools for studying GluN2A receptor function in vivo.

Main Methods:

• Chemical modification of the linker region in the MPX-004/MPX-007 scaffold.
• Synthesis and characterization of novel compounds targeting GluN2A receptors.
• Development of a radioligand and pharmacokinetic studies of lead compounds.

Main Results:

• Identified potent and selective GluN2A-targeting compounds with enhanced drug-like properties.
• Compound 1 enabled the creation of the first GluN2A negative allosteric modulator (NAM)-based radioligand.
• Compound 11 demonstrated improved pharmacokinetics and dose-dependent receptor occupancy in vivo.

Conclusions:

• The optimized scaffold provides novel tools for studying GluN2A receptors.
• These compounds offer potential for further research into NMDA receptor function and related disorders.
• The developed radioligand and pharmacokinetic data advance the study of GluN2A receptor modulation.