Design and synthesis of 6-methylpyridin-2-one derivatives as novel and potent GluN2A positive allosteric modulators for the treatment of cognitive impairment

[Display omitted] N-Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel serie...

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Published in:Bioorganic & medicinal chemistry 2023-02, Vol.79, p.117150-117150, Article 117150
Main Authors: Yukawa, Takafumi, Yamashita, Tohru, Imaeda, Toshihiro, Kakei, Hiroyuki, Hashizume, Shogo, Nakamura, Minoru, Daini, Masaki, Okabe, Atsutoshi, Nakashima, Kosuke, Harada, Akina, Narita, Naohiro, Bettini, Ezio, Ugolini, Annarosa, Corsi, Mauro, Hasui, Tomoaki
Format: Article
Language:English
Subjects:
6-methylpyridin-2-one
Animals
Cognitive Dysfunction - drug therapy
Cognitive Dysfunction - metabolism
GluN2A positive allosteric modulator (PAM)
Hippocampus - metabolism
Long-term potentiation (LTP)
N-methyl-D-aspartate receptor (NMDAR)
Rats
Receptors, N-Methyl-D-Aspartate - metabolism
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Summary:[Display omitted] N-Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel series of GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold. Initial lead compound 1 was discovered through in silico-based screening of virtual ligands with various monocyclic scaffolds. GluN2A PAM activity was increased by introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain. Modification of the aromatic ring led to the identification of potent and brain-penetrant 6-methylpyridin-2-one 17 with a negligible binding activity for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Oral administration of 17 significantly enhanced rat hippocampal long-term potentiation (LTP). Thus, 17 would be a useful in vivo pharmacological tool to investigate complex NMDAR functions for the discovery of therapeutics toward diseases associated with NMDAR dysfunction
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2022.117150