Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity

N-Methyl-D-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family and play a crucial role in learning and memory by regulating synaptic plasticity. Activation of NMDARs containing GluN2A, one of the NMDAR subunits, has been recently identified as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy.

Identification of a new hit for GluN2A PAMs is however difficult due to the similarity of PAM binding sites between GluN2A and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs), another member of the ionotropic glutamate receptor family.

In this collaborative publication with Takeda, we focus on:

• Identification of an hit compound with moderate AMPAR-binding activity, though a Ca²⁺ influx-based high throughput screening campaign with a compound set including an internal AMPAR-focused compound library
• The strategy using a structure-based drug design (SBDD) approach to minimize the AMPAR-binding activity while improving GluN2A activity
• The use of the potent and brain-penetrable GluN2A-selective positive allosteric modulators GluN2A PAM discovered as in vivo tool exhibiting significant neuroplastic enhancement in the rat hippocampus 24h after oral administration, having potential application for cognitive enhancement in neuropsychiatric diseases

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