scholarly journals In Vitro and In Vivo Pharmacological Comparison of Mu‐Opioid Receptor Activity of the Kratom ( Mitragyna speciosa ) Alkaloid Mitragynine and its Metabolite 7‐Hydroxymitragynine

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
Maria P Guerrero Calvache ◽  
Samuel Obeng ◽  
Francisco Leon ◽  
Lea R Gamez‐Jimenez ◽  
Avi Patel ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Receptor Activity ◽  
Mu Opioid ◽  
Mitragyna Speciosa

Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma

Life Sciences ◽  
2021 ◽  
Vol 278 ◽  
pp. 119541
Author(s):  
Aysegul Gorur ◽  
Miguel Patiño ◽  
Hideaki Takahashi ◽  
German Corrales ◽  
Curtis R. Pickering ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Opioid Receptor ◽  
Receptor Activation ◽  
Mu Opioid Receptor ◽  
Mu Opioid

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 In Vitro Effects of Ligand Bias on Primate Mu Opioid Receptor Downstream Signaling

2020 ◽  
Vol 21 (11) ◽  
pp. 3999
Author(s):  
Xiao Zhang ◽  
Shaurita D. Hutchins ◽  
Bruce E. Blough ◽  
Eric J. Vallender
Keyword(s):  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Luciferase Reporter ◽  
Response Curves ◽  
Mu Opioid ◽  
Biased Agonism ◽  
Downstream Signaling ◽  
Ligand Bias

Interest has emerged in biased agonists at the mu opioid receptor (MOR) as a possible means for maintaining potent analgesis with reduced side effect profiles. While approaches measuring in vitro biased agonism are used in the development of these compounds, their therapeutic utility will ultimately be determined by in vivo functional effects. Nonhuman primates (NHPs) are the most translational model for evaluating the behavioral effects of candidate medications, but biased signaling of these drugs at NHP MOR receptors has been unstudied. The goal of the current work was to characterize MOR ligand bias in rhesus macaques, focusing on agonists that have previously been reported to show different patterns of biased agonism in rodents and humans. Downstream signaling pathways that responded to MOR activation were identified using a luciferase reporter array. Concentration-response curves for specific pathways (cAMP, NF-ĸB, MAPK/JNK) were generated using six agonists previously reported to differ in terms of signaling bias at rodent and human MORs. Using DAMGO as a reference ligand, relative cAMP, NF-ĸB and MAPK/JNK signaling by morphine, endomorphin-1, and TRV130 were found to be comparable between species. Further, the bias patterns of across ligands for NF-ĸB and MAPK/JNK were largely similar between species. There was a high degree of concordance between rhesus macaque and human MOR receptor signaling bias for all agonists tested, further demonstrating their utility for future translational behavioral studies.

In vitro and in vivo activity of cyclopeptide Dmt-c[ d -Lys-Phe-Asp]NH 2 , a mu opioid receptor agonist biased toward β-arrestin

Peptides ◽  
2018 ◽  
Vol 105 ◽  
pp. 51-57 ◽  
Author(s):  
Katarzyna Gach-Janczak ◽  
Justyna Piekielna-Ciesielska ◽  
Anna Adamska-Bartłomiejczyk ◽  
Karol Wtorek ◽  
Federica Ferrari ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Opioid Receptor Agonist

In Vitro and In Vivo Assessment of Mu Opioid Receptor Constitutive Activity

2010 ◽  
pp. 413-443 ◽  
Author(s):  
Edward J. Bilsky ◽  
Denise Giuvelis ◽  
Melissa D. Osborn ◽  
Christina M. Dersch ◽  
Heng Xu ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Constitutive Activity ◽  
Mu Opioid ◽  
In Vivo Assessment

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 Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2087 ◽  
Author(s):  
Maria Dumitrascuta ◽  
Marcel Bermudez ◽  
Steven Ballet ◽  
Gerhard Wolber ◽  
Mariana Spetea
Keyword(s):  
Molecular Docking ◽  
Opioid Receptor ◽  
Rank Order ◽  
Opioid Peptide ◽  
Mu Opioid Receptor ◽  
In Vitro Assays ◽  
Peptide Ligand ◽  
Mu Opioid ◽  
Peptide Analogues

The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt1]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt1]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt1]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.

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