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title: Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity
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Read our collaborative paper with Takeda | Discovery of Pyrazolo[1,5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity | Contact Evotec to learn more"
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# Science Pool

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

Posted by [Evotec](https://news.cyprotex.com/sciencepool/author/evotec) on Dec 22, 2021 9:22:41 AM

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

[LEARN MORE](https://www.sciencedirect.com/science/article/pii/S0968089621005848)

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