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Title: Hot Topics in Opioid Pharmacology: Mixed and Biased Opioids.
Authors: Azzam, A. A. H.
McDonald, J.
Lambert, D. G
First Published: 2019
Publisher: Elsevier
Citation: British Journal of Anaesthesia, 2019, In Press
Abstract: 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.
ISSN: 0007-0912
Links: TBA
Embargo on file until: 1-Jan-10000
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © Elsevier 2019. After an embargo period this version of the paper will be an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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