Opioid Analgesics: Rise and Fall of Ligand Biased Signaling and Future Perspectives in the Quest for the Holy Grail

Opioid analgesics have been used for more than 5,000 years and remain the principal pain medications prescribed today. Although morphine is considered the gold standard for pain relief, this µ-opioid receptor (MOP)-selective agonist provides only moderate relief for many chronic pain conditions and promotes several unwanted effects that can adversely affect patient quality-of-life, prevent adherence to treatment or generate addiction. In addition to the lack of progress in the development of better analgesics, there have been no significant breakthroughs to date that have addressed side effects mentioned above. Fortunately, a better understanding of opioid pharmacology has restored hope for the development of better and safer pain medications. In this review, we describe how clinically approved opioids were initially characterized as biased ligands and what impact this approach could have on clinical practice. We also looked at the preclinical and clinical development of MOP biased agonists, with an emphasis on the oliceridine story, as the first specifically designed biased painkiller. Moreover, we explore the discrepancies between ligands with low intrinsic efficacy and those with biased properties. Finally, we examine the rationale behind biased ligand development during the opioid crisis era.

Pain; Opioids; Morphine; Biased Signaling; Functional Selectivity; G Protein; β-arrestin; G Protein-Coupled Receptors; GPCRs