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

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 mu, opioid receptor (R-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 mu-OR agonists have been reported to selectively activate the G(i) over beta-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased mu,-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand-receptor recognition process.