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 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.

Selective δ opioid receptor agonists for inflammatory and neuropathic pain

Il Farmaco ◽  
2001 ◽  
Vol 56 (1-2) ◽  
pp. 117-119 ◽  
Author(s):  
Giulio Dondio ◽  
Silvano Ronzoni ◽  
Carlo Farina ◽  
Davide Graziani ◽  
Carlo Parini ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Opioid Receptor ◽  
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.

Chemical Characterization and in vitro Metabolism of a Novel Class of Delta Opioid Receptor Agonists, Analogs of SNC-80

2019 ◽  
Vol 4 (7) ◽  
pp. 2109-2115
Author(s):  
Elisabetta Maria Usai ◽  
Ilaria Manca ◽  
Francesca Pettinau ◽  
Antonio Mastino ◽  
Barbara Pittau
Keyword(s):  
Opioid Receptor ◽  
Chemical Characterization ◽  
In Vitro Metabolism ◽  
Delta Opioid Receptor ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Homology modeling and 3D–QSAR study of benzhydrylpiperazine δ opioid receptor agonists

2019 ◽  
Vol 83 ◽  
pp. 107109 ◽  
Author(s):  
Chenling Pan ◽  
Hao Meng ◽  
Shuqun Zhang ◽  
Zhili Zuo ◽  
Yuehai Shen ◽  
...  
Keyword(s):  
Homology Modeling ◽  
Opioid Receptor ◽  
3D Qsar ◽  
Qsar Study ◽  
Receptor Agonists ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Differential Effects of μ-, δ-, and κ-Opioid Receptor Agonists on Mechanosensitive Gastric Vagal Afferent Fibers in the Rat

2000 ◽  
Vol 83 (4) ◽  
pp. 2209-2216 ◽  
Author(s):  
Noriyuki Ozaki ◽  
J. N. Sengupta ◽  
G. F. Gebhart
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Dose Range ◽  
Receptor Agonists ◽  
Afferent Fibers ◽  
Opioid Receptor Agonist ◽  
Resting Activity ◽  
Vagal Afferent ◽  
Δ Opioid Receptor ◽  
Opioid Receptor Agonists

Single-fiber recordings were made from the decentralized right cervical vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers that responded to gastric distension (GD) were studied: 6 fibers were stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave increasing responses to increasing pressures of GD (5–60 mmHg). The effects of μ-opioid (morphine), δ-opioid (SNC80), and κ-opioid (EMD61,753, U62,066) receptor agonists were tested on responses of afferent fibers to GD. Morphine, administered systemically over a broad dose range (10 μg to 31 mg/kg, cumulative), had no effect on either resting activity or responses of vagal afferent fibers to GD. Similarly, the δ-opioid receptor agonist SNC80 (0.05–3.2 mg/kg) did not affect resting activity or responses to GD. In contrast, cumulative intra-arterial doses of the κ-opioid receptor agonist EMD61,753 or U62,066 dose dependently attenuated afferent fiber responses to GD. Doses producing inhibition to 50% of the control response to GD of EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the κ-opioid receptor-selective antagonist nor-BNI (20 mg/kg) was ineffective. These results demonstrate that κ-, but not μ- or δ-opioid receptor agonists modulate visceral sensation conveyed by vagal afferent fibers innervating the stomach. Given that κ-opioid receptor agonists effects were only modestly antagonized by naloxone and not at all by nor-BNI, the results point to a novel site of action.

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