Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Structure-Activity Relationship and Functional Evaluation of Cannabinoid Type-1 Receptor

  • Shujie Wang (Pharmacology Laboratory, College of Pharmacy, Chonnam National University) ;
  • Xinru Tian (Pharmacology Laboratory, College of Pharmacy, Chonnam National University) ;
  • Suresh Paudel (Pharmacology Laboratory, College of Pharmacy, Chonnam National University) ;
  • Sungho Ghil (Department of Life Science, Kyonggi University) ;
  • Choon-Gon Jang (Pharmacology Laboratory, College of Pharmacy, Sungkyunkwan University) ;
  • Kyeong-Man Kim (Pharmacology Laboratory, College of Pharmacy, Chonnam National University)
  • Received : 2023.11.17
  • Accepted : 2023.12.26
  • Published : 2024.07.01
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Abstract

The type-1 cannabinoid receptor (CB1R) is a potential therapeutic target in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Owing to their structural diversity, it is not easy to derive general structure-activity relationships (SARs) for CB1R ligands. In this study, CB1R ligands were classified into six structural families, and the corresponding SAR was determined for their affinities for CB1R. In addition, we determined their functional activities for the activation of extracellular signal-regulated kinases (ERKs). Among derivatives of indol-3-yl-methanone, the highest ligand affinity was observed when a pentyl and a naphthalenyl group were attached to the N1 position of the indole ring and the carbon site of the methanone moiety, respectively. In the case of adamantane indazole-3-carboxamide derivatives, the presence of fluorine in the pentyl group, the substituent at the N1 position of the indazole ring, strongly increased the affinity for CB1R. For (naphthalen-1-yl) methanone derivatives, the presence of 4-alkoxynaphthalene in the methanone moiety was more beneficial for the affinity to CB1R than that of a heterocyclic ring. The functional activities of the tested compounds, evaluated through ERK assay, were correlated with their affinity for CB1R, suggesting their agonistic nature. In conclusion, this study provides valuable insight for designing novel ligands for CB1R, which can be used to control psychiatric disorders and drug abuse.

Keywords

Acknowledgement

This research was supported by the Ministry of Food and Drug Safety (19182MFDS403) and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00239943).

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