Hot Topics in Opioid Pharmacology: Mixed and Biased Opioids.

Analgesic design and evaluation has been driven by the desire to create high affinity, high selectivity MOP (mu;µ) agonists. Such ligands are the mainstay of current clinical practice and include morphine and fentanyl. Advances in this sphere have come from designing pharmacokinetic advantage; rapid metabolism for remifentanil. These produce analgesia but also the adverse effect profile that currently defines this drug class; namely ventilatory depression, tolerance and abuse liability. The MOP receptor is part of a family and there are significant functional interactions between other members of the family (DOP;delta;δ, KOP;kappa;κ and NOP;nociceptin/orphanin FQ). Experimentally MOP agonism and DOP antagonism produced antinociception (animals) with no tolerance and low doses of MOP and NOP ligands synergize to antinociceptive advantage. In this latter context lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low selectivity multifunctional ‘mixed ligands’ (e.g., Cebranopadol) or ligand mixtures (e.g., Targinact). Moreover, the observation that β-arrestin coupling underlies the side effect profile for MOP ligands (from knockout animal studies) led to the discovery of biased (to G-protein and away from β-arrestin) MOP ligands (e.g., oliceridine). There is sufficient excitement in the opioid field to suggest that opioid analgesics without significant side effects may be on the horizon and the ‘opioid holy grail’ might be in reach

Pharmacological Characterization of μ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

In recent years, G protein vs. β-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of µ-opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe-pCF3-Phe-Asp]NH2 (F-81), and the β-arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35S]GTPγS binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure β-arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand–receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or β-arrestin