Breaking point: A cannabinoid type 2 receptor agonist prodrug has been developed, that can be rapidly cleaved upon exposure to λ=450–455 nm light. This prodrug has significantly reduced receptor binding compared to the released chromenopyrazole agonist. The coumarin products produced in the prodrug photolysis varied in different solvents and light conditions.
G protein-coupled receptor (GPCR) ligand prodrugs that can be released on demand with spatiotemporal control are powerful chemical tools that can assist in elucidating the consequences of GPCR activation or blockade at precise locations and times both in vitro and in vivo. Cannabinoid receptor prodrugs are of interest from both a drug delivery perspective and as tools to unravel the potential for differential signaling responses to be produced from cannabinoid receptor populations in distinct subcellular locations. Herein, the development and characterization of a cannabinoid type 2 receptor agonist prodrug is described, based on a 4-diethylamino-coumarylidenemalononitrilemethyl (DEACM-MN) photo caging moiety linked via a carbonate to a chromenopyrazole cannabinoid ligand. This prodrug showed rapid photolysis with 450–455 nm light and good stability in biologically relevant buffer. The formation of various coumarin products alongside drug release was studied in different conditions. Radioligand binding assays were conducted with the prodrug, which revealed a significantly decreased human cannabinoid type 2 receptor binding affinity than the active chromenopyrazole parent ligand.Zum Volltext