Biased mu-opioid receptor ligands: a promising new generation of pain therapeutics

•Biased MOR ligands discovered using empirical, rational and natural product approaches.•Biased MOR ligands produce analgesia with fewer side effects in mice and humans.•βArr2 KO successfully predicted G protein biased ligand pharmacology in rodents.•In vitro data on biased MOR agonists translate to human pharmacology.

Opioid chemistry and biology occupy a pivotal place in the history of pharmacology and medicine. Morphine offers unmatched efficacy in alleviating acute pain, but is also associated with a host of adverse side effects. The advent of biased agonism at G protein-coupled receptors has expanded our understanding of intracellular signaling and highlighted the concept that certain ligands are able to differentially modulate downstream pathways. The ability to target one pathway over another has allowed for the development of biased ligands with robust clinical efficacy and fewer adverse events. In this review we summarize these concepts with an emphasis on biased mu opioid receptor pharmacology and highlight how far opioid pharmacology has evolved.