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.
Highlights
Agonists of the μ-opioid receptor (MOR), such as morphine and the synthetic opioid fentanyl, are mainstay analgesics for the treatment for severe acute pain
We demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling and -arrestin recruitment for all tested ligands
The MOR is predominantly coupled to the Gi/o protein family, which signals by inhibiting the production of cyclic AMP by adenylyl cyclase (AC) via G -subunits, and activating G protein–coupled inwardly rectifying potassium (GIRK) channels through G subunits, among other effectors [1] [1]
Summary
Agonists of the μ-opioid receptor (MOR), such as morphine and the synthetic opioid fentanyl, are mainstay analgesics for the treatment for severe acute pain. Similar to most other G protein–coupled receptors (GPCRs), MOR signalling is regulated by the phosphorylation of intracellular C-terminal serine and threonine residues, which stabilizes the binding of arrestins. Studies showed enhanced morphine analgesia in -arrestin 2 knockout mice with greatly diminished respiratory depression and constipation [2, 3] This has led to the hypothesis that a putative arrestin-dependent mechanism downstream of the MOR mediates the unwanted side effects of opioids [4]. The nature of this proposed signal altering respiratory and gastrointestinal function has not been demonstrated This ‘arrestin hypothesis’ has been challenged by the persistence of morphine- and fentanylinduced side effects, including respiratory depression and constipation, in a knock -in mouse expressing a phospho-deficient MOR mutant that is unable to recruit -arrestin [5] as well as by the persistence of morphineinduced respiratory depression in the a -arrestin 2 knockout mouse [6][6] (Kliewer et al Br J Pharmacol In press). There is robust physiological evidence demonstrating that classical G protein signaling from the MOR contributes substantially to respiratory depression [7, 8], as well as to other side effects, such as constipation [9, 10]
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