Critical Assessment of G Protein-Biased Agonism at the μ-Opioid Receptor

被引：105

作者：

Gillis, Alexander ^{[1
,6
]}

Kliewer, Andrea ^{[2
,6
]}

Kelly, Eamonn ^{[3
]}

Henderson, Graeme ^{[3
]}

Christie, Macdonald J. ^{[1
]}

Schulz, Stefan ^{[2
]}

Canals, Meritxell ^{[4
,5
,6
]}

机构：

[1] Univ Sydney, Sch Med Sci, Discipline Pharmacol, Sydney, NSW, Australia

[2] Friedrich Schiller Univ, Jena Univ Hosp, Inst Pharmacol & Toxicol, Jena, Germany

[3] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol, Avon, England

[4] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Div Physiol Pharmacol & Neurosci, Nottingham, England

[5] Univ Birmingham, Ctr Membrane Prot & Receptors, Birmingham, W Midlands, England

[6] Univ Nottingham, Ctr Membrane Prot & Receptors, Nottingham, England

来源：

TRENDS IN PHARMACOLOGICAL SCIENCES | 2020年 / 41卷 / 12期

基金：

英国医学研究理事会;

关键词：

GUINEA-PIG; MICE LACKING; RESPIRATORY DEPRESSION; INTRINSIC EFFICACY; MORPHINE-TOLERANCE; POTASSIUM CHANNELS; LIGAND BIAS; NEURONS; ANALGESICS; TRV130;

D O I：

10.1016/j.tips.2020.09.009

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

G protein-biased agonists of the mu-opioid receptor (MOPr) have been proposed as an improved class of opioid analgesics. Recent studies have been unable to reproduce the original experiments in the beta-arrestin2-knockout mouse that led to this proposal, and alternative genetic models do not support the G protein-biased MOPr agonist hypothesis. Furthermore, assessment of putatively biased ligands has been confounded by several factors, including assay amplification. As such, the extent to which current lead compounds represent mechanistically novel, extremely G protein-biased agonists is in question, as is the underlying assumption that beta-arrestin2 mediates deleterious opioid effects. Addressing these current challenges represents a pressing issue to successfully advance drug development at this receptor and improve upon current opioid analgesics.

引用

页码：947 / 959

页数：13

共 86 条

[1] Blockade by pertussis toxin of the opioid effect on guinea pig ileum. Contractility and electrophysiological neuronal recording [J].