Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools

Azobenzene-embedded
photoswitchable ligands are the widely used
chemical tools in photopharmacological studies. Current approaches
to azobenzene introduction rely mainly on the isosteric replacement
of typical azologable groups. However, atypical scaffolds may offer
more opportunities for photoswitch remodeling, which are chemically
in an overwhelming majority. Herein, we investigate the rational remodeling
of atypical scaffolds for azobenzene introduction, as exemplified
in the development of photoswitchable ligands for the cannabinoid
receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding
the binding pocket, we conclude that among the three representative
atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is
the most appropriate for azobenzene remodeling. The optimizing spacer
length and attachment position revealed AzoLig 9 with
excellent thermal bistability, decent photopharmacological switchability
between its two configurations, and high subtype selectivity. This
structure-guided approach gave new impetus in the extension of new
chemical spaces for tool customization for increasingly diversified
photo-pharmacological studies and beyond.