Skip to main content

Research Repository

Advanced Search

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

Gillis, Alexander; Gondin, Arisbel B.; Kliewer, Andrea; Sanchez, Julie; Lim, Herman D.; Alamein, Claudia; Manandhar, Pradeep; Santiago, Marina; Fritzwanker, Sebastian; Schmidel, Frank; Katte, Timothy A.; Reekie, Tristan; Grimsey, Natasha L.; Kassiou, Michael; Kellam, Barrie; Krasel, Cornelius; Halls, Michelle L.; Connor, Mark; Lane, J. Robert; Schulz, Stefan; Christie, Macdonald J.; Canals, Meritxell

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


Alexander Gillis

Arisbel B. Gondin

Andrea Kliewer

Research Fellow - Pharmacology Cell Biologist

Herman D. Lim

Claudia Alamein

Pradeep Manandhar

Marina Santiago

Sebastian Fritzwanker

Frank Schmidel

Timothy A. Katte

Tristan Reekie

Natasha L. Grimsey

Michael Kassiou

Profile Image

Professor of Medicinal Chemistry

Cornelius Krasel

Michelle L. Halls

Mark Connor

Associate Professor

Stefan Schulz

Macdonald J. Christie


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.

Journal Article Type Article
Acceptance Date Mar 6, 2020
Online Publication Date Mar 31, 2020
Publication Date Mar 31, 2020
Deposit Date Mar 23, 2020
Publicly Available Date Mar 31, 2020
Journal Science Signaling
Print ISSN 1945-0877
Electronic ISSN 1937-9145
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 13
Issue 625
Article Number eaaz3140
Keywords Cell Biology; Biochemistry; Molecular Biology
Public URL
Publisher URL
Additional Information This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling on Vol. 13 31 March 2020, DOI: 10.1126/scisignal.aaz3140


You might also like

Downloadable Citations