Alkyl indole-based cannabinoid type 2 receptor tools: Exploration of linker and fluorophore attachment

Cannabinoid type 2 (CB₂) receptor continues to emerge as a promising drug target for many diseases and conditions. New tools for studying CB₂ receptor are required to further inform how this receptor functions in healthy and diseased states. The alkyl indole scaffold is a well-recognised ligand for cannabinoid receptors, and in this study the indole C5-7 positions were explored for linker and fluorophore attachment. A new high affinity, CB₂ receptor selective inverse agonist was identified (16b) along with a general trend of C5-substituted indoles acting as agonists versus C7-substituted indoles acting as inverse agonists. The indole C7 position was found to be the most tolerant to linker extension and resulted in a high affinity inverse agonist with a medium length linker (19). Although a high affinity fluorescent ligand for CB₂ receptor was not identified in this study, the indole C7 position shows great promise for fluorophore or probe attachment.