A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

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Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

Pharmacological Reports ◽

10.1007/s43440-021-00251-1 ◽

2021 ◽

Author(s):

Lucja Kudla ◽

Ryszard Przewlocki

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Intracellular Signaling ◽

Opioid Analgesics ◽

Opioid Addiction ◽

Receptor Agonists ◽

Biased Signaling ◽

Μ Opioid Receptor ◽

Opioid Receptor Agonists

AbstractOpioid analgesics remain a gold standard for the treatment of moderate to severe pain. However, their clinical utility is seriously limited by a range of adverse effects. Among them, their high-addictive potential appears as very important, especially in the context of the opioid epidemic. Therefore, the development of safer opioid analgesics with low abuse potential appears as a challenging problem for opioid research. Among the last few decades, different approaches to the discovery of novel opioid drugs have been assessed. One of the most promising is the development of G protein-biased opioid agonists, which can activate only selected intracellular signaling pathways. To date, discoveries of several biased agonists acting via μ-opioid receptor were reported. According to the experimental data, such ligands may be devoid of at least some of the opioid side effects, such as respiratory depression or constipation. Nevertheless, most data regarding the addictive properties of biased μ-opioid receptor agonists are inconsistent. A global problem connected with opioid abuse also requires the search for effective pharmacotherapy for opioid addiction, which is another potential application of biased compounds. This review discusses the state-of-the-art on addictive properties of G protein-biased μ-opioid receptor agonists as well as we analyze whether these compounds can diminish any symptoms of opioid addiction. Finally, we provide a critical view on recent data connected with biased signaling and its implications to in vivo manifestations of addiction. Graphic abstract

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Molecular Modeling of µ Opioid Receptor Ligands with Various Functional Properties: PZM21, SR-17018, Morphine, and Fentanyl—Simulated Interaction Patterns Confronted with Experimental Data

Molecules ◽

10.3390/molecules25204636 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4636 ◽

Cited By ~ 2

Author(s):

Sabina Podlewska ◽

Ryszard Bugno ◽

Lucja Kudla ◽

Andrzej J. Bojarski ◽

Ryszard Przewlocki

Keyword(s):

Molecular Modeling ◽

G Protein ◽

Opioid Receptor ◽

Pearson Correlation ◽

Interaction Patterns ◽

Receptor Ligands ◽

Opioid Receptor Ligands ◽

Dynamics Simulations

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor.

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Molecular Dynamics Simulations to Investigate How PZM21 Affects the Conformational State of the μ-Opioid Receptor Upon Activation

International Journal of Molecular Sciences ◽

10.3390/ijms21134699 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4699 ◽

Cited By ~ 2

Author(s):

Zhennan Zhao ◽

Tingting Huang ◽

Jiazhong Li

Keyword(s):

Molecular Dynamics ◽

Side Effects ◽

G Protein ◽

Opioid Receptor ◽

Conformational Changes ◽

Opioid Analgesics ◽

Dynamics Simulation ◽

Analgesic Effects ◽

Μ Opioid Receptor ◽

Dynamics Simulations

Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W2936.48 (Ballesteros–Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W3187.35, Y3267.43, and Y3367.53 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR–ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.

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Delineating the Ligand–Receptor Interactions That Lead to Biased Signaling at the μ-Opioid Receptor

Journal of Chemical Information and Modeling ◽

10.1021/acs.jcim.1c00585 ◽

2021 ◽

Author(s):

Brendan Kelly ◽

Scott A. Hollingsworth ◽

David C. Blakemore ◽

Robert M. Owen ◽

R. Ian Storer ◽

...

Keyword(s):

Opioid Receptor ◽

Receptor Interactions ◽

Biased Signaling ◽

Μ Opioid Receptor

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Selective utilization of G‐protein coupled receptor kinase (GRK) 2 and 3 in morphine‐induced μ opioid receptor internalization

The FASEB Journal ◽

10.1096/fasebj.22.2_supplement.617 ◽

2008 ◽

Vol 22 (S2) ◽

pp. 617-617

Author(s):

Kelly M. Standifer ◽

Vanessa I. Ramirez

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Receptor Internalization ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Μ Opioid Receptor ◽

G Protein Coupled

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Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

International Journal of Molecular Sciences ◽

10.3390/ijms21228463 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8463

Author(s):

Damian Bartuzi ◽

Ewa Kędzierska ◽

Agnieszka A. Kaczor ◽

Helmut Schmidhammer ◽

Dariusz Matosiuk

Keyword(s):

Opioid Receptor ◽

In Silico ◽

Antinociceptive Effect ◽

In Vivo Studies ◽

Allosteric Modulators ◽

Allosteric Site ◽

Μ Opioid Receptor ◽

Dynamics Simulations ◽

Higher Doses

Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation. In this study, molecular dynamics simulations in silico and ‘writhing’ tests in vivo were used to characterize potential allosteric mechanism of two previously reported compounds. The results suggest that investigated compounds bind to μ opioid receptor in an allosteric site, augmenting action of morphine at subeffective doses, and exerting antinociceptive effect alone at higher doses. Detailed analysis of in silico calculations suggests that first of the compounds behaves more like allosteric agonist, while the second compound acts mainly as a positive allosteric modulator.

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