JWH-015

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.

Cannabinoids bind to cannabinoid receptors CB1 and CB2 and their antitumoral activity has been reported against some various cancer cell lines. Some synthetic cannabinoids possessing indole rings such as JWH-015 and JWH-133 particularly bind to the cannabinoid CB2 receptor and it was reported that they inhibit the proliferation and growth of various cancer cells without their psychoactive effects. However, the pharmacological action mechanisms of the cannabinoids are completely unknown. In this study, we report the synthesis of some new cannabinoidic novel indoles and evaluate their anticancer activity on various cancerous and normal cell lines (U87, RPMI 8226, HL60 and L929) using several cellular and molecular assays including MTT assay, real-time q-PCR, scratch assay, DAPI assay, Annexin V-PE/7AAD staining, caspase3/7 activity tests. Our findings indicated that compounds 7, 10, 13, 16, and 17 could reduce cell viability effectively. Compound 17 markedly increased proapoptotic genes (BAX, BAD, and BIM), tumor suppressor gene (p53) expression levels as well as the BAX/BCL-2 ratio in U87 cells. In addition, 17 inhibited cell migration. Based on these results, 17 was chosen for determining the mechanism of cell death in U87 cells. DAPI and Annexin V-7AAD staining results showed that 17 induced apoptosis, moreover activated caspase 3/7 significantly. Hence, compound 17, was selected as a lead compound for further pharmacomodulation. To rationalize the observed biological activities of 17, our study also included a comprehensive analysis using molecular docking and MD simulations. This integrative approach revealed that 17 fits tightly into the active site of the CB2 receptor and is involved in key interactions that may be responsible for its anti-proliferative effects.