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, Justyna; Artali, Roberto; Azzam, Ammar A H; Lambert, David G.; Kluczyk, Alicja; Gentilucci, Luca; Janecka, Anna

doi:10.3390/molecules26010013

Cited by 12 publications

(11 citation statements)

References 81 publications

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“…Protein–ligand complexes from selected docked poses were minimized in explicit TIP3P water molecules and equilibrated by molecular dynamics. More details can be found in the literature [ 52 ] and in the experimental section. The overlay of KW-495 and KW-496 into KOP is illustrated in Figure S6 , and shows that the two peptide conjugates occupy the same cavity of the receptor, albeit with distinct orientations.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors

Wtorek

Ghidini

Gentilucci

et al. 2022

IJMS

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Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors

Wtorek

Ghidini

Gentilucci

et al. 2022

IJMS

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“…Indeed, several studies supported that κ-OR plays an important role in cancer development by promoting or inhibiting tumor growth and metastasis and influencing patient prognosis. These observations demonstrated that κ-OR is upregulated in various types of solid tumors, such as liver, colon, non-small cell lung cancer, and other malignancies, and its expression is associated with cancer growth and a poor prognosis [24][25][26].…”

Section: Biological Effects 241 Effect Of the Amides On Cell Viabilitymentioning

confidence: 88%

Synthesis and Antiproliferative Activity against Cancer Cells of Indole-Aryl-Amide Derivatives

et al. 2022

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Indoles constitute a large family of heterocyclic compounds widely occurring in nature which are present in a number of bioactive natural and synthetic compounds, including anticancer agents or atypical opioid agonists. As a result, exponential increases in the development of novel methods for the synthesis of indole-containing compounds have been reported in the literature. A series of indole-aryl amide derivatives 1–7 containing tryptamine or an indolylacetic acid nucleus were designed, synthesized, and evaluated as opioid ligands. These new indole derivatives showed negligible to very low affinity for μ- and δ-opioid receptor (OR). On the other hand, compounds 2, 5, and 7 showed Ki values in the low μM range for κ-OR. Since indoles are well known for their anticancer potential, their effect against a panel of tumor cell lines was tested. The target compounds were evaluated for their in vitro cytotoxicity in HT29, HeLa, IGROV-1, MCF7, PC-3, and Jurkat J6 cells. Some of the synthesized compounds showed good activity against the selected tumor cell lines, with the exception of IGROV1. In particular, compound 5 showed a noteworthy selectivity towards HT29 cells, a malignant colonic cell line, without affecting healthy human intestinal cells. Further studies revealed that 5 caused the cell cycle arrest in the G1 phase and promoted apoptosis in HT29 cells.

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“…Molecular dynamics simulations (MDS) reveal additional 7TMR conformations. Distinct intracellular pocket conformations have been observed in simulations of μOR complexes with a wide variety of ligands 21,[26][27][28][29] . We hypothesized that signaling efficacy is linearly proportional to the equilibrium population of these intracellular receptor conformations.…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesized that signaling efficacy is linearly proportional to the equilibrium population of these intracellular receptor conformations. To test this hypothesis, we first performed simulations of μOR complexed with 11 ligands from a variety of chemical series, comprising the most comprehensive set of agonists in a single study to date (previous studies 21,[26][27][28][29] included up to 5 complexes). We tested this hypothesis by developing a machine learning model that categorizes configurations from MDS into conformations.…”

Section: Introductionmentioning

confidence: 99%

Intracellular pocket conformations determine signaling efficacy through the μ opioid receptor

Cooper,

DePaolo-Boisvert,

Nicholson

et al. 2024

Preprint

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The relationship between the binding of a ligand to a receptor and activation of biological signaling pathways has remained unclear. The challenge is compounded by functional selectivity, in which a single ligand binding to a single receptor can activate multiple signaling pathways at different levels. Spectroscopic studies show that in the largest class of cell surface receptors, 7 transmembrane receptors, activation is associated with shifts in the equilibria of intracellular pocket conformations. We hypothesized that signaling through the μ opioid receptor, a prototypical 7TMR, is linearly proportional to the equilibrium probability of observing intracellular pocket conformations. Here we show that a machine learning model based on this hypothesis accurately calculates the efficacy of both G protein and β-arrestin-2 signaling. Structural features that the model associates with activation are intracellular pocket expansion, toggle switch rotation, and sodium binding pocket collapse. Distinct pathways are activated by different arrangements of the ligand and sodium binding pockets and the intracellular pocket. Our study provides the first evidence for what could be a scientific law. While recent work has categorized ligands as active or inactive (or partially active) based on binding affinities to two conformations, our approach accurately computes signaling efficacy along multiple pathways.

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

Cited by 12 publications

References 81 publications

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors

Synthesis and Antiproliferative Activity against Cancer Cells of Indole-Aryl-Amide Derivatives

Intracellular pocket conformations determine signaling efficacy through the μ opioid receptor

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