scholarly journals In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 6079
Author(s):  
Yusuke Karasawa ◽  
Kanako Miyano ◽  
Hideaki Fujii ◽  
Takaaki Mizuguchi ◽  
Yui Kuroda ◽  
...  
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Peptides ◽  
Opioid Analgesics ◽  
Receptor Agonists ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKeyTM assay, cADDis® cAMP assay, and PathHunter® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKeyTM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis® cAMP and PathHunter® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.

scholarly journals Modulating β Arrestin-2 Recruitment at the δ- and μ-Opioid Receptors

2020 ◽  
Author(s):  
Krishna Sharma ◽  
Robert Cassell ◽  
HongYu Su ◽  
Arryn Blaine ◽  
Benjamin Cummins ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonists ◽  
C Terminus ◽  
Biased Signaling ◽  
Receptor Pharmacology ◽  
Pharmacology And Toxicology ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Opioid receptors can trigger two distinct pathways (G protein coupling and arrestin recruitment) that differentially regulate a host of desired and undesired pharmacological effects. Increasingly, “biased” opioids that selectively activate one pathway over the other are being developed to treat disorders in which µ- and κ-opioids receptors are involved, though the development of biased δ-opioid receptor agonists has remained rather quiescent. Herein, we identify the C-terminus of Tyr-ψ[(<i>Z</i>)CF=CH]-Gly-Leu-enkephalin as a key site to regulate bias of both δ- and µ-opioid receptor agonists. Using <i>in vitro</i> assays, substitution of the Leu<sup>5</sup> carboxylate reduced β-arrestin recruitment through both the δ- and µ-opioid receptors in a predictable structure-dependent fashion, while retaining affinity and cAMP potency comparable to the C-terminal carboxylate. These substitutions should enable discovery of a range of tool compounds for exploring δ-opioid receptor pharmacology and toxicology, which will enable reevaluation of this target within the context of biased signaling.

scholarly journals Modulating β Arrestin-2 Recruitment at the δ- and μ-Opioid Receptors

2020 ◽  
Author(s):  
Krishna Sharma ◽  
Robert Cassell ◽  
HongYu Su ◽  
Arryn Blaine ◽  
Benjamin Cummins ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonists ◽  
C Terminus ◽  
Biased Signaling ◽  
Receptor Pharmacology ◽  
Pharmacology And Toxicology ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Opioid receptors can trigger two distinct pathways (G protein coupling and arrestin recruitment) that differentially regulate a host of desired and undesired pharmacological effects. Increasingly, “biased” opioids that selectively activate one pathway over the other are being developed to treat disorders in which µ- and κ-opioids receptors are involved, though the development of biased δ-opioid receptor agonists has remained rather quiescent. Herein, we identify the C-terminus of Tyr-ψ[(<i>Z</i>)CF=CH]-Gly-Leu-enkephalin as a key site to regulate bias of both δ- and µ-opioid receptor agonists. Using <i>in vitro</i> assays, substitution of the Leu<sup>5</sup> carboxylate reduced β-arrestin recruitment through both the δ- and µ-opioid receptors in a predictable structure-dependent fashion, while retaining affinity and cAMP potency comparable to the C-terminal carboxylate. These substitutions should enable discovery of a range of tool compounds for exploring δ-opioid receptor pharmacology and toxicology, which will enable reevaluation of this target within the context of biased signaling.

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

EVIDENCE FOR A CENTRAL OPIOID CONTROL OF RUMINATION

1984 ◽  
Vol 64 (5) ◽  
pp. 13-15 ◽  
Author(s):  
Y. RUCKEBUSCH ◽  
TH. BARDON
Keyword(s):  
Key Words ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Opioid Peptides ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Receptor Agonists ◽  
Opioid Agonists ◽  
Reflex Control ◽  
Opioid Receptor Agonists

Intravenous adrenaline induced reticular extracontractions and rumination within 26 sec in hay-fed, and 184 sec in cube-fed sheep. Regardless of diet, pretreatment with cerebroventricular infusion of kappa-opioid-receptor agonists enhanced this reflex. Control of rumination may involve multiple opioid-receptors, since inhibition of the reflex occurred after mu- and delta-opioid-agonists. Key words: Sheep, rumination, opioid-peptides

New Diarylmethylpiperazines as Potent and Selective Nonpeptidic δ Opioid Receptor Agonists with Increased In Vitro Metabolic Stability

2000 ◽  
Vol 43 (21) ◽  
pp. 3878-3894 ◽  
Author(s):  
Niklas Plobeck ◽  
Daniel Delorme ◽  
Zhong-Yong Wei ◽  
Hua Yang ◽  
Fei Zhou ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Metabolic Stability ◽  
Receptor Agonists ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

scholarly journals 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects

2021 ◽  
Author(s):  
Nicholas S. Akins ◽  
Nisha Mishra ◽  
Hannah M. Harris ◽  
Narendar Dudhipala ◽  
Seong Jong Kim ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Analgesic Activity ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold <i>via</i> an ester linker. <i>In vitro</i> studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. <i>In vivo </i>studies on the lead dual kappa and mu opioid receptor agonist, compound <b>10</b>, showed that it<b> </b>produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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

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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