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

Abstract

Cannabinoid type 2 (CB₂) receptor has been implicated in several diseases and conditions, however no CB₂ receptor selective drugs have made it to market. The aim of this study was to develop fluorescent ligands as CB₂ receptor tools, to enable an increased understanding of CB₂ 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 CB₂ receptor. A series of 1,8-naphthyridin-2-(1<i>H</i>)-one-3-carboxamides with linkers and fluorophores appended in the N1 and C3-positions were developed. Molecular modelling indicated the C3 <i>cis</i>-cyclohexanol-linked compounds directed the linker out of the CB₂ receptor between transmembrane helices 1 and 7. Herein we report fluorescent ligand <b>32</b> (hCB₂ p<i>K</i> _i = 6.33 ± 0.02) as one of the highest affinity, selective CB₂ receptor fluorescent ligands reported. Despite <b>32</b> displaying poor specific labelling of CB₂ receptor, the naphthyridine scaffold with this linker remains highly promising for future development of CB₂ receptor tools.