Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

• Published in: Drug discovery today Vol. 22; no. 11; pp. 1719 - 1729
• Main Authors: Madariaga-Mazón, Abraham, Marmolejo-Valencia, Andrés F., Li, Yangmei, Toll, Lawrence, Houghten, Richard A., Martinez-Mayorga, Karina
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-11-2017
• Subjects: Acute Pain - drug therapy; Analgesics, Opioid - adverse effects; Analgesics, Opioid - pharmacology; Animals; Drug Design; Drug Discovery - methods; Humans; Ligands; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - metabolism; Signal Transduction - drug effects
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2017.07.002

•μ-OR biased agonists represent promising analgesics with improved therapeutic profiles.•Protein-ligand interactions might account for biased ligands functional selectivity.•Databases of μ-OR ligands may be a valuable source to rescue missing biased agonists.
Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased μ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand–receptor recognition process.