dc.contributor.author |
Gillis Alexander |
en |
dc.contributor.author |
Gondin Arisbel B |
en |
dc.contributor.author |
Kliewer Andrea |
en |
dc.contributor.author |
Sanchez Julie |
en |
dc.contributor.author |
Lim Herman D |
en |
dc.contributor.author |
Alamein Claudia |
en |
dc.contributor.author |
Manandhar Preeti |
en |
dc.contributor.author |
Santiago Marina |
en |
dc.contributor.author |
Fritzwanker Sebastian |
en |
dc.contributor.author |
Schmiedel Frank |
en |
dc.contributor.author |
Katte Timothy A |
en |
dc.contributor.author |
Reekie Tristan |
en |
dc.contributor.author |
Grimsey Natasha L |
en |
dc.contributor.author |
Kassiou Michael |
en |
dc.contributor.author |
Kellam Barrie |
en |
dc.contributor.author |
Krasel Cornelius |
en |
dc.contributor.author |
Halls Michelle L |
en |
dc.contributor.author |
Connor Mark |
en |
dc.contributor.author |
Lane J Robert |
en |
dc.contributor.author |
Schulz Stefan |
en |
dc.contributor.author |
Christie Macdonald J |
en |
dc.contributor.author |
Canals Meritxell |
en |
dc.date.accessioned |
2020-10-12T02:51:46Z |
|
dc.date.available |
2020-10-12T02:51:46Z |
|
dc.date.issued |
2020-3-31 |
en |
dc.identifier.issn |
1945-0877 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/53228 |
|
dc.description.abstract |
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 β-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 β-arrestin recruitment. At the μ-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 β-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 β-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. |
en |
dc.format.medium |
Electronic |
en |
dc.language |
eng |
en |
dc.publisher |
AMER ASSOC ADVANCEMENT SCIENCE |
en |
dc.relation.ispartofseries |
Science signaling |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
1115 Pharmacology and Pharmaceutical Sciences |
en |
dc.subject |
Biomedical |
en |
dc.subject |
Substance Abuse |
en |
dc.subject |
Neurosciences |
en |
dc.subject |
Chronic Pain |
en |
dc.subject |
Drug Abuse (NIDA only) |
en |
dc.subject |
Pain Research |
en |
dc.subject |
Science & Technology |
en |
dc.subject |
Life Sciences & Biomedicine |
en |
dc.subject |
Biochemistry & Molecular Biology |
en |
dc.subject |
Cell Biology |
en |
dc.subject |
INVESTIGATING OLICERIDINE TRV130 |
en |
dc.subject |
COUPLED RECEPTOR KINASE |
en |
dc.subject |
LIGAND BIAS |
en |
dc.subject |
RESPIRATORY DEPRESSION |
en |
dc.subject |
MICE LACKING |
en |
dc.subject |
BUPRENORPHINE |
en |
dc.subject |
MORPHINE |
en |
dc.subject |
MODERATE |
en |
dc.subject |
SAFETY |
en |
dc.subject |
NORBUPRENORPHINE |
en |
dc.subject |
0601 Biochemistry And Cell Biology |
en |
dc.title |
Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1126/scisignal.aaz3140 |
en |
pubs.issue |
625 |
en |
pubs.volume |
13 |
en |
dc.date.updated |
2020-09-08T04:39:49Z |
en |
dc.rights.holder |
Copyright: The author |
en |
pubs.author-url |
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000523190200003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=6e41486220adb198d0efde5a3b153e7d |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
798277 |
en |
dc.identifier.eissn |
1937-9145 |
en |
pubs.number |
ARTN eaaz3140 |
en |