Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Structure-Activity Relationship of NMDA Receptor Ligands and Their Activities on the ERK Activation through Metabotropic Signaling Pathway

  • Dooti Kundu (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Mengling Wang (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Suresh Paudel (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Shujie Wang (Department of Pharmacology, College of Pharmacy, Chonnam National University) ;
  • Choon-Gon Jang (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Kyeong-Man Kim (Department of Pharmacology, College of Pharmacy, Chonnam National University)
  • Received : 2024.11.10
  • Accepted : 2025.01.16
  • Published : 2025.03.01
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Abstract

The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00239943) and by the Ministry of Food and Drug Safety of Korea (23212MFDS218).

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