Photoswitchable allosteric and dualsteric ligands in GPCR pharmacology

G protein-coupled receptors (GPCRs) regulate numerous pathophysiological processes and have traditionally been modulated at the orthosteric site. Targeting allosteric sites offers an alternative approach that can enhance selectivity, modulate signal bias, and reduce side effects. Photopharmacology enables precise spatial and temporal drug control of receptors by light using modified drug molecules incorporating chemical photoswitches, especially azobenzenes. Allosteric and dualsteric photoswitchable ligands, the latter targeting both orthosteric and allosteric sites, are being developed - to date mainly at metabotropic glutamate (mGlu), muscarinic acetylcholine (mACh or M), and cannabinoid (CB) receptors, since their allosteric sites have been described in the most detail and with the largest number of respective allosteric ligands developed. The novel ligands can photocontrol even more refined GPCR functions, like signal bias and degrees of partial agonism. This review describes the recent development for these GPCRs in allosteric and dualsteric photoswitchable ligands, highlighting the specific challenging design, which is even more complex than for orthosteric photoswitchable ligands, since structure-activity relationships (SARs) are steep and often insufficiently described, and spacer structures strongly influence binding.