Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator

Area of Science:

• Neuroscience
• Medicinal Chemistry

Background:

• Glutamate is crucial for cognition and mood.
• Inhibiting ionotropic glutamate receptors impairs cognition; enhancing activity is pro-cognitive.
• Antagonizing presynaptic metabotropic glutamate receptor 2 (mGluR2) can elevate glutamatergic tone.

Purpose of the Study:

• To identify selective mGluR2 negative allosteric modulators (NAMs) for therapeutic applications.
• To develop compounds with improved potency, selectivity, and safety profiles.

Main Methods:

• Screening and optimization of 4-arylquinoline-2-carboxamides.
• Structure-activity relationship studies for potency and off-target effects.
• Metabolic profiling and Ames testing to assess genetic toxicity.

Main Results:

• A novel series of 4-arylquinoline-2-carboxamides with mGluR2 NAM activity was identified.
• Optimization led to improved potency and physical properties.
• Initial compounds showed Ames positivity; further optimization yielded the Ames-negative MK-8768.

Conclusions:

• MK-8768 is a potent, selective, and non-genotoxic mGluR2 NAM.
• This compound represents a promising therapeutic candidate for cognitive and mood disorders.