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

Abstract

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 G_i 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.

FIGURE 1

Graphical representation of the functional selectivity concept at mu-opioid receptors (μ-ORs). (a) Chemical space of μ-OR ligands (blue dots) represented in a principal component analysis (PCA) plot according to relevant drug-likeness properties. Biased agonists are under-represented and fall in the same area (red dots). (b) Classical opiates, such as morphine, bind to the μ-OR and produce analgesia (mainly via the G-protein pathway) with the concomitant triggering of parallel signaling cascades (β-arrestin pathway) responsible for the adverse effects. (c) Biased agonists that are capable of preferentially activate the G-protein signaling pathway over the arrestin pathway produce analgesia with diminished adverse effects.

FIGURE 2

Binding model of biased ligands and the classical opiates at mu-opioid receptors (μ-ORs). (a) Surface representation of the binding site for classical opiates (green) and biased ligands (orange). (b) Detail of binding model for biased ligands represented by herkinorin (light-orange sticks). Morphine is shown for reference (yellow sticks). (c) Predicted binding modes of biased ligands.

FIGURE 3

Protein-ligand interaction fingerprints (PLIF) profile of mu-opioid receptor (μ-OR) ligands. (a) Population histogram and (b) chemical space of μ-OR ligands in the ChEMBL database. (c) Population histogram and (d) chemical space (orange dots) of filtered ligands from the ChEMBL database based on the proposed interactions corresponding to the biased profile.

FIGURE I

Timeline of the discovery of biased ligands.