Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

Waal, Parker W. de; Shi, Jingjing; You, Erli; Wang, Xiaoxi; Melcher, Karsten; Jiang, Yi; Xu, H. Eric; Dickson, Bradley M.

doi:10.1371/journal.pcbi.1007394

Cited by 47 publications

(67 citation statements)

References 56 publications

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“…Following in-silico computations accelerated by the use of mollified adaptive biasing potential, they proposed a mechanism where fentanyl mediates MOP β-arrestin through a peculiar microswitch of the position of Met (3.36). This residue is pushed downward by fentanyl's n-aniline ring, to adopt a rotameric conformation which directly displaces Trp(6.48) [68].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

Piekielna-Ciesielska

Artali²,

Azzam

et al. 2020

Molecules

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In recent years, G protein vs. β-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of µ-opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe-pCF3-Phe-Asp]NH2 (F-81), and the β-arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35S]GTPγS binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure β-arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand–receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or β-arrestin.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

Piekielna-Ciesielska

Artali²,

Azzam

et al. 2020

Molecules

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“…The residue was identified to directly interact with ligands’ N–aniline ring and its conformational change affected the rotameric state of W295 6.48 residue. The findings were further validated by design and synthesis of novel fentanyl based derivatives with confirmed complete, clinically desirable, G i protein biased coupling [ 52 ].…”

Section: Opioid Receptorsmentioning

confidence: 99%

“…The authors postulated the switch to be critical for receptor activation and the ligand interactions that positioned the two residues influenced the increased or decreased signaling via β-arrestin. In more recent molecular modeling study de Waal et al employed adaptively biased MD simulations to determine the molecular mechanisms of interactions between μ-OR system and fentanyl and two its derivatives, highly potent β-arrestin biased agonists [ 52 ]. The authors proposed an activation mechanism where agonist molecules mediated β-arrestin signaling of μ-OR through a novel M153 3.36 “microswitch” at the ortosteric site.…”

Section: Opioid Receptorsmentioning

confidence: 99%

Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

Jóźwiak

Płazińska

2021

Molecules

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G protein-coupled receptors (GPCRs) are versatile signaling proteins that mediate complex cellular responses to hormones and neurotransmitters. Ligand directed signaling is observed when agonists, upon binding to the same receptor, trigger significantly different configuration of intracellular events. The current work reviews the structurally defined ligand – receptor interactions that can be related to specific molecular mechanisms of ligand directed signaling across different receptors belonging to class A of GPCRs. Recent advances in GPCR structural biology allow for mapping receptors’ binding sites with residues particularly important in recognition of ligands’ structural features that are responsible for biased signaling. Various studies show particular role of specific residues lining the extended ligand binding domains, biased agonists may alternatively affect their interhelical interactions and flexibility what can be translated into intracellular loop rearrangements. Studies on opioid and angiotensin receptors indicate importance of residues located deeper within the binding cavity and direct interactions with receptor residues linking the ortosteric ligand binding site with the intracellular transducer binding domain. Collection of results across different receptors may suggest elements of common molecular mechanisms which are responsible for passing alternative signals from biased agonists.

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“…It is not unexpected that perceptions of bias and efficacy will vary between studies ( 19, 37 ). In time, the value of these cellular readouts as predictors of agonist function may be supported by detecting state-dependent structural conformations of MOR induced by biased ligands binding to the receptor ( 38–40 ). From a practical standpoint, however, the correlation between the pharmacological properties and the improvement in therapeutic efficacy while limiting side effects in human studies should drive further investigations.…”

Section: Tablementioning

confidence: 99%

Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists

Stahl

Bohn

2020

Preprint

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In a recent report by Gillis et al., 2020 (1), it was suggested that low intrinsic agonism, and not biased agonism, leads to an improvement in the separation of potency in opioid-induced respiratory suppression versus antinociception. Although the compounds that were tested have been shown to display G protein signaling bias in prior publications, the authors conclude that since they cannot detect biased agonism in their cellular signaling studies the compounds are therefore not biased agonists. Rather, they conclude that it is low intrinsic efficacy that leads to the therapeutic window improvement. Intrinsic efficacy is the extent to which an agonist can stimulate a G protein-coupled receptor (GPCR) response in a system. The designation of full agonist is made to compounds that produce the highest observable activation in a system (maximum intrinsic efficacy); agonists producing some fraction of that response are considered partial agonists. The maximum response window is determined by the cellular environment, receptor and effector expression levels, and the amplification readout of the system. Biased agonism takes into consideration not only intrinsic efficacy, but also potency (concentration required to reach half maximal efficacy) of an agonist in an assay. Herein, the data published in the aforementioned manuscript was used to rederive the intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50). Based on this reanalysis, the data does not support the conclusion that biased agonism, favoring G protein signaling, was not present. Further, these observations agree with prior studies wherein oliceridine, PZM21 and SR-17018 were first described as biased agonists with improvement in antinociception over respiratory suppression in mice. Therefore, introducing G protein signaling bias may be a means to improve opioid analgesia while avoiding certain undesirable side effects.

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Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

Cited by 47 publications

References 56 publications

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation

Structural Insights into Ligand—Receptor Interactions Involved in Biased Agonism of G-Protein Coupled Receptors

Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists

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