A Surprising Recipe for Designing Biased Ligands.

The determination of the potential value of receptor trafficking at melanocortin receptors has been hampered by the absence of known biased ligands. Heterobivalent MC4R ligands linking agonist to antagonist small peptidic moieties were designed and found to act as Gαs enhancers while minimally activating β-arrestin recruitment. The strategy invoked offers intriguing promise as a surprising approach that is possibly broadly applicable to the challenge of designing biased ligands at other GPCRs.