In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator

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 via an ester linker. In vitro 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. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it 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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21113999 ◽

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.

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

Alzheimer s & Dementia ◽

10.1002/alz.058605 ◽

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

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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 ◽

10.1016/j.peptides.2018.04.014 ◽

2018 ◽

Vol 105 ◽

pp. 51-57 ◽

Cited By ~ 9

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

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

Methods in Enzymology - Constitutive Activity in Receptors and Other Proteins, Part A ◽

10.1016/b978-0-12-381298-8.00021-6 ◽

2010 ◽

pp. 413-443 ◽

Cited By ~ 4

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

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

10.26434/chemrxiv.14204834 ◽

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 via an ester linker. In vitro 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. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it 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.

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