Unlocking Selenium Chemical Space via a Programmable Synthesis Platform Bearing Cannabinoid Receptor Recognition...

Developing synthetic methods that allow controllable homologation to quickly access new chemical space is vital yet remains challenging for studying biological pathways. Utilizing underexplored elements as biological probes offers promising platforms to reveal uncharted aspects of G-protein-coupled receptor (GPCR) pharmacology. Here we report the development of an expeditious, sustainable platform for the scalable conversion of chloro-imidoylsulfonylureas, to provide one-pot access to synthetically versatile chiral, pro-chiral and achiral selenosulfonyl homologated compounds bearing the cannabinoid receptor-1 (CB₁R) recognition motifs. The synthetic route was designed using Na₂SeSO₃, a benign selenium source under aqueous conditions to enable the target-oriented synthesis of novel seleno-cannabinoid agents labeled as SelenoCanns. This Bunte-reaction-inspired seleno-homologation opens the door for on-demand synthesis of bioactive organoselenium drug-like molecules, covalent-drug conjugates, click handles, and seleno-fluorescent probes, thus opening a vast space of previously inaccessible molecules for expanded structure-function studies on the CB₁R. Of the new chemotypes discovered and synthesized, many compounds showed nanomolar to sub-nanomolar binding affinity for the CB1 receptor.