Discovery of Pyrazolo[1, 5-a]pyrazin-4-ones as Potent and Brain Penetrant GluN2A-Selective Positive Allosteric Modulators Reducing AMPA Receptor Binding Activity. (15th February 2022)

• Record Type: Journal Article
• Authors: Sakurai, Fumie; Yukawa, Takafumi; Kina, Asato; Murakami, Masataka; Takami, Kazuaki; Morimoto, Sachie; Seto, Masaki; Kamata, Makoto; Yamashita, Tohru; Nakashima, Kosuke; Narita, Naohiro; Bettini, Ezio; Ugolini, Annarosa; Corsi, Mauro; Hasui, Tomoaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 56(2022)
• Publication Date: 2022-02-15
• Subjects: N-methyl-d-aspartate receptor (NMDAR) -- Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) -- GluN2A -- NR2A -- Pyrazolo[1, 5-a]pyrazin-4-one -- Positive allosteric modulator -- Long-term potentiation (LTP); AMPAR amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor -- CNS central nervous system -- iGluR ionotropic glutamate receptor -- LBD ligand-binding domain -- LHS left-hand side -- LLE ligand-lipophilicity efficiency -- LTP long-term potentiation -- NMDAR N-methyl-d-aspartate receptor -- PAM positive allosteric modulators -- RHS right-hand side -- SAR structure–activity relationship -- SBDD structure-based drug design -- SPA scintillation proximity assay -- TPSA topological polar surface area; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116576
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 recently attracted attention as a promising therapeutic approach for neuropsychiatric diseases such as schizophrenia, depression, and epilepsy. In the present study, we developed potent and brain-penetrable GluN2A-selective positive allosteric modulators. Lead compound 2b was generated by scaffold hopping of hit compound 1, identified from the internal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-focused compound library through a high-throughput screening campaign. Subsequent optimization of the lead compound, including a structure-based drug design approach, resulted in the identification of a potent GluN2A PAM ( R )-9, which possessed high selectivity against both subtypes of AMPAR and NMDAR. Furthermore, ( R )-9 significantly enhanced long-term potentiation in the rat hippocampus 24 h after oral administration, indicating that this molecule is a potentially useful in vivo pharmacological tool for treating psychiatric diseases.