Masuho, I. et al. Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci. Signal. 8, ra123 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Lamberts, J. T., Jutkiewicz, E. M., Mortensen, R. M. & Traynor, J. R. mu-Opioid receptor coupling to Gαo plays an important role in opioid antinociception. Neuropsychopharmacology 36, 2041–2053 (2011).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Stanley, T. H. The history and development of the fentanyl series. J. Pain Symptom Manag. 7, S3–S7 (1992).

Article  CAS  Google Scholar 

Bot, G., Blake, A. D., Li, S. & Reisine, T. Fentanyl and its analogs desensitize the cloned mu opioid receptor. J. Pharmacol. Exp. Ther. 285, 1207–1218 (1998).

PubMed  CAS  Google Scholar 

Schmid, C. L. et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175 (2017).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Chakraborty, S. et al. A novel mitragynine analog with low-efficacy mu opioid receptor agonism displays antinociception with attenuated adverse effects. J. Med. Chem. 64, 13873–13892 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Meert, T. F., Lu, H. R., van Craenndonck, H. & Janssen, P. A. Comparison between epidural fentanyl, sufentanil, carfentanil, lofentanil and alfentanil in the rat: analgesia and other in vivo effects. Eur. J. Anaesthesiol. 5, 313–321 (1988).

PubMed  CAS  Google Scholar 

Prozialeck, W. C., Jivan, J. K. & Andurkar, S. V. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J. Am. Osteopath. Assoc. 112, 792–799 (2012).

PubMed  Google Scholar 

Kruegel, A. C. et al. 7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent. Sci. 5, 992–1001 (2019).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kamble, S. H. et al. Metabolism of a kratom alkaloid metabolite in human plasma increases its opioid potency and efficacy. ACS Pharmacol. Transl. Sci. 3, 1063–1068 (2020).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Chakraborty, S. et al. Oxidative Metabolism as a Modulator of Kratom’s Biological Actions. J. Med. Chem. 64, 16553–16572. https://doi.org/10.1021/acs.jmedchem.1c01111(2021).

Varadi, A. et al. Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. J. Med. Chem. 59, 8381–8397 (2016).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Conibear, A. E. & Kelly, E. A biased view of μ-opioid receptors? Mol. Pharmacol. 96, 542–549 (2019).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Bohn, L. M., Gainetdinov, R. R., Lin, F. T., Lefkowitz, R. J. & Caron, M. G. μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408, 720–723 (2000).

Article  PubMed  CAS  Google Scholar 

Groer, C. E. et al. An opioid agonist that does not induce μ-opioid receptor–arrestin interactions or receptor internalization. Mol. Pharmacol. 71, 549–557 (2007).

Article  PubMed  CAS  Google Scholar 

DeWire, S. M. et al. A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708–717 (2013).

Article  PubMed  CAS  Google Scholar 

Manglik, A. et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 537, 185–190 (2016).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Gillis, A. et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signal. https://doi.org/10.1126/scisignal.aaz3140 (2020).

Bachmutsky, I., Wei, X. P., Durand, A. & Yackle, K. β-arrestin 2 germline knockout does not attenuate opioid respiratory depression. eLife 10, e62552 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kliewer, A. et al. Phosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects. Nat. Commun. 10, 1–11 (2019).

Article  Google Scholar 

He, L. et al. Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice. Neuropsychopharmacology https://doi.org/10.1038/s41386-021-01054-x (2021).

Raffa, R. B., Martinez, R. P. & Connelly, C. D. G-protein antisense oligodeoxyribonucleotides and μ-opioid supraspinal antinociception. Eur. J. Pharmacol. 258, R5–R7 (1994).

Article  PubMed  CAS  Google Scholar 

Leck, K. J. et al. Deletion of guanine nucleotide binding protein αz subunit in mice induces a gene dose dependent tolerance to morphine. Neuropharmacology 46, 836–846 (2004).

Article  PubMed  CAS  Google Scholar 

Olsen, R. H. et al. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat. Chem. Biol. 16, 841–849 (2020).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhou, Y. et al. Predicted mode of binding to and allosteric modulation of the μ-opioid receptor by kratom’s alkaloids with reported antinociception in vivo. Biochemistry 60, 1420–1429 (2021).

Article  PubMed  CAS  Google Scholar 

Robertson, M. J., van Zundert, G. C., Borrelli, K. & Skiniotis, G. GemSpot: a pipeline for robust modeling of ligands into cryo-EM maps. Structure 28, 707–716 (2020).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Koehl, A. et al. Structure of the μ-opioid receptor–Gi protein complex. Nature 558, 547–552 (2018).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ballesteros, J. A. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. in Methods in Neurosciences, Vol. 25 (Elsevier, 1995).

Huang, W. et al. Structural insights into µ-opioid receptor activation. Nature 524, 315–321 (2015).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Manglik, A. et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature 485, 321–326 (2012).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Friesner, R. A. et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. J. Med. Chem. 49, 6177–6196 (2006).

Article  PubMed  CAS  Google Scholar 

Mahinthichaichan, P., Vo, Q. N., Ellis, C. R. & Shen, J. Kinetics and mechanism of fentanyl dissociation from the μ-opioid receptor. JACS Au 1, 2208–2215 (2021).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wingler, L. M. & Lefkowitz, R. J. Conformational basis of G protein-coupled receptor signaling versatility. Trends Cell Biol. 30, 736–747 (2020).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Suomivuori, C. M. et al. Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor. Science 367, 881–887 (2020).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Grim, T. W., Acevedo-Canabal, A. & Bohn, L. M. Toward directing opioid receptor signaling to refine opioid therapeutics. Biol. Psychiatry 87, 15–21 (2020).

Article  PubMed  CAS  Google Scholar 

Faouzi, A., Varga, B. R. & Majumdar, S. Biased opioid ligands. Molecules https://doi.org/10.3390/molecules25184257 (2020).

Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017).

Article  PubMed  CAS  Google Scholar 

Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife https://doi.org/10.7554/eLife.42166 (2018).

Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhang, K. Gctf: real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016).

Article  PubMed  PubMed Central  CAS  Google Scholar 

Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

Article