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Essential role of P-glycoprotein in the mechanism of action of oliceridine

Abstract

Mu opioid receptor (MOR) agonists comprise the most effective analgesics, but their therapeutic utility is limited by adverse effects. One approach for limiting such effects has been to develop “biased” MOR agonists that show preference for activating G protein over β-Arrestin signaling. However, the notion of biased agonism has been challenged by recent studies. Oliceridine (Olinvyk®, TRV-130, OLC) is a selective MOR agonist approved by the FDA in 2020 for pain management in controlled clinical settings. Oliceridine purportedly demonstrates diminished adverse effects compared to morphine or other MOR agonists, a profile attributed to its biased agonism. However, recent studies suggest that oliceridine does not display biased agonism but instead weak intrinsic efficacy for G protein and β-Arrestin activation. Nevertheless, these insights have been derived from in vitro studies. To better understand oliceridine’s in vivo efficacy profile, we performed a comprehensive assessment of its in vitro and in vivo pharmacology using both cultured cells and rodents. In vitro, oliceridine displayed high MOR affinity and weak intrinsic efficacy. In vivo, oliceridine showed impaired brain penetrance and rapid clearance, effects we attributed to its interaction with the P-glycoprotein (P-gp) efflux transporter. Moreover, we found that P-gp was essential for oliceridine’s in vivo efficacy and adverse effect profiles. Taken together with prior studies, our results suggest that oliceridine’s in vivo efficacy and adverse effect profiles are not attributed solely to its weak intrinsic efficacy or biased agonism but, to a large extent, its interaction with P-gp as well.

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Fig. 1: Oliceridine binds MOR with high affinity but does not stimulate [35 S]GTPγS recruitment in brain tissue.
Fig. 2: Synthesis and characterization of [3H]oliceridine.
Fig. 3: Oliceridine exhibits rapid MOR occupancy.
Fig. 4: Oliceridine’s brain uptake is determined by its interaction with P-glycoprotein.
Fig. 5: P-glycoprotein is a critical determinant of oliceridine’s efficacy and adverse effects.

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Acknowledgements

We thank Dr. Renata Marchette, Dr. Leandro Vendruscolo, and Dr. George Koob for access to instrumentation, Dr. Víctor Fernandez-Dueñas, Dr Francisco Ciruela and Dr. Kazuki Horikawa for providing biosensor cDNA’s and to Dr. Yavin Shaham and Dr. Amy Newman for access to resources.

Funding

This work was supported by the NIDA Intramural Research Program (ZIA000069 (MM) and the Medication Development Program) and by Grants RYC-2019-027371-I (JB) funded by MCIN/AEI /10.13039/501100011033 and by “ESF Investing in your future” and 2021I070 (JB) funded by the Plan Nacional Sobre Drogas.

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JB, ENV, MM, and RR designed the experiments. JB, ENV, AR, JLG, OS, SL, and JF conducted the experiments. JB, ENV, AR, JLG, SL, and JF performed the data analysis. JB, ENV, and MM wrote the manuscript. All authors contributed to manuscript feedback.

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Correspondence to Jordi Bonaventura or Michael Michaelides.

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MM has received research funding from AstraZeneca, Redpin Therapeutics and Attune Neurosciences. All other authors declare no conflicts of interest.

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Ventriglia, E., Rizzo, A., Gomez, J.L. et al. Essential role of P-glycoprotein in the mechanism of action of oliceridine. Neuropsychopharmacol. 48, 831–842 (2023). https://doi.org/10.1038/s41386-022-01507-x

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