scholarly journals A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects

2021 ◽  
Author(s):  
Soumen Chakraborty ◽  
Jeffrey F Diberto ◽  
Abdelfattah Faouzi ◽  
Sarah M bernhard ◽  
Anna M Gutridge ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Ex Vivo ◽  
Mu Opioid Receptor ◽  
Place Conditioning ◽  
Mu Opioid ◽  
Synaptic Physiology ◽  
Protein Assays ◽  
Efficacy Profile

Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom and its natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal beta-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and beta-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.

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

Some effects of putative G-protein biased mu-opioid receptor agonists in male rhesus monkeys

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Jeremy C. Cornelissen ◽  
Bruce E. Blough ◽  
Laura M. Bohn ◽  
S. Stevens Negus ◽  
Matthew L. Banks
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Rhesus Monkeys ◽  
Mu Opioid Receptor ◽  
Mu Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists ◽  
Male Rhesus

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.

scholarly journals A Computationally Designed Water-Soluble Variant of a G-Protein-Coupled Receptor: The Human Mu Opioid Receptor

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66009 ◽  
Author(s):  
Jose Manuel Perez-Aguilar ◽  
Jin Xi ◽  
Felipe Matsunaga ◽  
Xu Cui ◽  
Bernard Selling ◽  
...  
Keyword(s):  
G Protein ◽  
Opioid Receptor ◽  
Mu Opioid Receptor ◽  
Water Soluble ◽  
G Protein Coupled Receptor ◽  
Mu Opioid ◽  
G Protein Coupled

scholarly journals Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids

2020 ◽  
Author(s):  
Simone Creed ◽  
Anna Gutridge ◽  
Malaika Argade ◽  
Madeline Hennessy ◽  
J. Brent Friesen ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Biological Evaluation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Traditional Use ◽  
Pharmacological Characterization ◽  
Thermal Nociception ◽  
Mu Opioid ◽  
Opioid Receptor Agonist

<p>The seeds of the akuamma tree (<i>Picralima nitida</i>) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography is developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine, pseudo-akuammigine, picraline, akuammicine, and akuammiline, were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed<i> in vitro </i>investigations revealed one alkaloid as a potent kappa opioid receptor agonist and three alkaloids with micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the akuamma alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which to develop novel opioids with unique pharmacologically properties and therapeutic utility. <b><br></b></p>

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.

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