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

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 ß-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 ß-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 ß-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 ß-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.

Morphine-induced respiratory depression is independent of ß-arrestin2 signalling.

BACKGROUND AND PURPOSE: GPCRs can signal through both G proteins and ß-arrestin2. For the µ-opioid receptor, early experimental evidence from a single study suggested that G protein signalling mediates analgesia, whereas ß-arrestin2 signalling mediates respiratory depression and constipation. Consequently, for more than a decade, much research effort has been focused on developing biased µ-opioid agonists that preferentially target G protein signalling over ß-arrestin signalling, as it was believed that such drugs would be analgesics devoid of respiratory depressant activity. However, the prototypical compounds that have been developed based on this concept have so far failed in clinical and preclinical development. EXPERIMENTAL APPROACH: The present study was set up to re-examine opioid-induced respiratory depression in ß-arrestin2 knockout mice. To this end, a consortium was formed consisting of three different laboratories located in different countries to evaluate independently opioid-induced respiratory depression. KEY RESULTS: Our consensus results unequivocally demonstrate that the prototypical µ-opioid agonist morphine (3.75-100 mg·kg-1 s.c. or 3-30 mg·kg-1 i.p.) as well as the potent opioid fentanyl (0.05-0.35 mg·kg-1 s.c.) do indeed induce respiratory depression and constipation in ß-arrestin2 knockout mice in a dose-dependent manner indistinguishable from that observed in wild-type mice. CONCLUSION AND IMPLICATIONS: Our findings do not support the original suggestion that ß-arrestin2 signalling plays a key role in opioid-induced respiratory depression and call into question the concept of developing G protein-biased µ-opioid receptor agonists as a strategy for the development of safer opioid analgesic drugs.