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

In recent years, G protein vs. ß-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 ß-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 ß-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 ß-arrestin.

Hot topics in opioid pharmacology: mixed and biased opioids.

Analgesic design and evaluation have been driven by the desire to create high-affinity high-selectivity mu (µ)-opioid peptide (MOP) receptor 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, as in rapid metabolism for remifentanil. These produce analgesia, but also the adverse-effect profile that currently defines this drug class: 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 (delta [δ]-opioid peptide [DOP], kappa [κ]-opioid peptide [KOP], and nociceptin/orphanin FQ receptor [NOP]). Experimentally, MOP agonism and DOP antagonism produce anti-nociception (animals) with no tolerance, and low doses of MOP and NOP ligands synergise to antinociceptive advantage. In this latter context, the lack of effect of NOP agonists on ventilation is an additional advantage. Recent development has been to move towards low-selectivity multifunctional 'mixed ligands', such as cebranopadol, or ligand mixtures, such as Targinact®. Moreover, the observation that ß-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 ß-arrestin intracellular signalling) MOP ligands, such as 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.

Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain.

INTRODUCTION: Opioids acting at the MOP (mu:µ) receptor produce analgesia but also side effects. There is debate suggesting opioid receptors produce analgesia via G-protein and side-effects via ß-arrestin-2 pathways. Opioids targeting G-proteins over the arrestins (bias) offer potential therapeutic advantages. Oliceridine is a putative MOP, G-protein biased agonist. AREAS COVERED: Oliceridine is selective for MOP receptors with greater activity at G-proteins over arrestins. A substantial body of evidence now points to a simpler pharmacological descriptor of partial agonist. Preclinical in vivo data indicates a robust antinociceptive response of shorter duration than morphine. Apollo trials (Phase-III RCT-bunionectomy/abdominoplasty) describe good analgesic efficacy that was non-inferior to morphine with good tolerability and side-effect profile. There is evidence for an improved respiratory safety profile. Oliceridine is approved by the FDA. EXPERT OPINION: Oliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Respiratory advantage and the possibility of reduced abuse potential are possible advantages over the use of traditional opioids. Based on a number of excellent, highly detailed studies, oliceridine should be described as a partial agonist; this 'label' does not matter.