Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

被引：231

作者：

Gillis, Alexander ^{[1
]}

Gondin, Arisbel B. ^{[2
]}

Kliewer, Andrea ^{[3
]}

Sanchez, Julie ^{[2
,4
,5
,6
]}

Lim, Herman D. ^{[2
]}

Alamein, Claudia ^{[1
]}

Manandhar, Preeti ^{[7
]}

Santiago, Marina ^{[7
]}

Fritzwanker, Sebastian ^{[3
]}

Schmidel, Frank ^{[3
]}

Katte, Timothy A. ^{[8
]}

Reekie, Tristan ^{[8
]}

Grimsey, Natasha L. ^{[9
]}

Kassiou, Michael ^{[8
]}

Kellam, Barrie ^{[10
]}

Krasel, Cornelius ^{[11
]}

Halls, Michelle L. ^{[2
]}

Connor, Mark ^{[7
]}

Lane, J. Robert ^{[4
,5
,6
]}

Schulz, Stefan ^{[3
]}

Christie, Macdonald J. ^{[1
]}

Canals, Meritxell ^{[2
,4
,5
,6
]}

机构：

[1] Univ Sydney, Sch Med Sci, Discipline Pharmacol, Sydney, NSW 2006, Australia

[2] Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol Theme, Parkville, Vic 3052, Australia

[3] Friedrich Schiller Univ, Jena Univ Hosp, Inst Pharmacol & Toxicol, D-07747 Jena, Germany

[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, Midlands, England

[7] Macquarie Univ, Dept Biomed Sci, Sydney, NSW 2109, Australia

[8] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia

[9] Univ Auckland, Fac Med & Hlth Sci, Sch Med Sci, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand

[10] Univ Nottingham, Ctr Biomol Sci, Sch Pharm, Nottingham NG7 2RD, England

[11] Philipps Univ Marburg, Dept Pharmacol & Toxicol, D-35043 Marburg, Germany

来源：

SCIENCE SIGNALING | 2020年 / 13卷 / 625期

基金：

英国医学研究理事会;

关键词：

INVESTIGATING OLICERIDINE TRV130; COUPLED RECEPTOR KINASE; LIGAND BIAS; RESPIRATORY DEPRESSION; MICE LACKING; BUPRENORPHINE; MORPHINE; MODERATE; SAFETY; NORBUPRENORPHINE;

D O I：

10.1126/scisignal.aaz3140

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Biased agonism at G protein-coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus beta-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as beta-arrestin recruitment. At the beta-opioid receptor (MOR), G protein-biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in beta-arrestin-mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and beta-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.

引用

页数：18

共 71 条

[21] Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression [J].