Orthosteric/allosteric bitopic ligands: going hybrid at GPCRs

G protein-coupled receptors (GPCRs) can adopt multiple biologically active states that can be differentially stabilized by ligands that bind to topographically distinct sites (e.g., orthosteric ligands and allosteric modulators). Recent studies in the field are now demonstrating the utility of linking orthosteric and allosteric pharmacophores to yield hybrid, or bitopic, ligands, with improved affinity and/or receptor subtype selectivity. Interestingly, this approach can also engender functional selectivity in the actions of orthosteric ligands, highlighting a viable means of further sculpting GPCR ligand responses. Indeed, some previously identified functionally selective agonists may actually represent hitherto unappreciated bitopic ligands.