Biomolecules & Therapeutics
Structure–Activity Relationship and Functional Evaluation of Cannabinoid Type-1 Receptor
Shujie Wang1,†, Xinru Tian1,†, Suresh Paudel1, Sungho Ghil2, Choon-Gon Jang3 and Kyeong-Man Kim1,*
1Pharmacology Laboratory, College of Pharmacy, Chonnam National University, Gwangju 61186,
2Department of Life Science, Kyonggi University, Suwon 16227,
3Pharmacology Laboratory, College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
Tel: +82-62-530-2936, Fax: +82-62-530-2949
The first two authors contributed equally to this work.
Received: November 17, 2023; Revised: December 15, 2023; Accepted: December 26, 2023; Published online: June 7, 2024.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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: Cannabinoid type 1 receptor, Structure-activity relationship, ERK, Ligand affinity, G protein

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