Development of selective, fluorescent cannabinoid type 2 receptor ligands based on a 1,8-naphthyridin-2-(1H)-one-3-carboxamide scaffold.

Cannabinoid type 2 (CB(2)) receptor has been implicated in several diseases and conditions, however no CB(2) receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB(2) receptor tools, to enable an increased understanding of CB(2) receptor expression and signalling and thereby accelerate drug discovery. Fluorescent ligands have been successfully developed for other receptors, however none with adequate subtype selectivity or imaging properties have been reported for CB(2) receptor. A series of 1,8-naphthyridin-2-(1H)-one-3-carboxamides with linkers and fluorophores appended in the N1 and C3-positions were developed. Molecular modelling indicated the C3 cis-cyclohexanol-linked compounds directed the linker out of the CB(2) receptor between transmembrane helices 1 and 7. Herein we report fluorescent ligand 32 (hCB(2) pK (i) = 6.33 ± 0.02) as one of the highest affinity, selective CB(2) receptor fluorescent ligands reported. Despite 32 displaying poor specific labelling of CB(2) receptor, the naphthyridine scaffold with this linker remains highly promising for future development of CB(2) receptor tools.