Photoswitchable allosteric and dualsteric ligands in GPCR pharmacology
Photopharmacology is used to enable precise G protein-coupled receptors (GPCRs) modulation by light and offers new opportunities to study receptor function, neural circuits, and even behavioral responses with unprecedented temporal and spatial resolution.
Such GPCR activation is achieved by both affinity- and efficacy photoswitchable ligands.
Photoswitchable allo- and dualsteric ligands enlarge the toolbox of GPCR photopharmacology; addressing the allosteric site or both allo- and orthosteric binding sites (dualsteric binding) can specifically modify receptor response, such as graded receptor activation (tuned ‘efficacy switching’), mimicking or enhancing the endogenous tone, and control signaling bias toward either G-protein or β-arrestin pathways.
Since new allosteric binding sites at GPCRs are increasingly postulated and described, specifically designing new allo- and dualsteric light-controllable ligands has significant potential to enlarge the GPCR photopharmacological toolbox, but the medicinal chemical design of such ligands provides additional challenges, for example, regarding the spacer length and structure, the selection of suitable parent ligands, and attachment locations in the molecules.
https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(25)00099-9
