scholarly journals Design, Synthesis, and Biological Evaluation of 14-Heteroaromatic-Substituted Naltrexone Derivatives: Pharmacological Profile Switch from Mu Opioid Receptor Selectivity to Mu/Kappa Opioid Receptor Dual Selectivity

2013 ◽  
Vol 56 (22) ◽  
pp. 9156-9169 ◽  
Author(s):  
Yunyun Yuan ◽  
Saheem A. Zaidi ◽  
Orgil Elbegdorj ◽  
Lindsey C. K. Aschenbach ◽  
Guo Li ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Biological Evaluation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Pharmacological Profile ◽  
Design Synthesis ◽  
Receptor Selectivity ◽  
Mu Opioid ◽  
Synthesis And Biological Evaluation ◽  
Opioid Receptor Selectivity

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>

Design, Synthesis, and Biological Evaluation of C6-Difluoromethylenated Epoxymorphinan Mu Opioid Receptor Antagonists

2021 ◽  
Author(s):  
Andrew Kassick ◽  
Anny Treat ◽  
Nestor Tomycz ◽  
Michael Feasel ◽  
Benedict Kolber ◽  
...  
Keyword(s):  
Substance Use ◽  
Biological Evaluation ◽  
Mu Opioid Receptor ◽  
High Potency ◽  
Design Synthesis ◽  
Mu Opioid ◽  
Synthetic Opioids ◽  
Opioid Receptor Antagonists ◽  
Synthesis And Biological Evaluation

The recent widespread abuse of high potency synthetic opioids, such as fentanyl, presents a serious threat to individuals affected by substance use disorder. Synthetic opioids generally exhibit prolonged in vivo...

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 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.

In major depression, increased kappa and mu opioid receptor levels are associated with immune activation

2020 ◽  
Vol 32 (2) ◽  
pp. 99-108 ◽  
Author(s):  
Hussein Kadhem Al-Hakeim ◽  
Suhaer Zeki Al-Fadhel ◽  
Arafat Hussein Al-Dujaili ◽  
Michael Maes
Keyword(s):  
Opioid Receptor ◽  
Immune Activation ◽  
Mu Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Receiver Operating Curve ◽  
Primary Immune Response ◽  
Mu Opioid ◽  
Simultaneous Activation ◽  
Drug Free ◽  
Inflammatory System

AbstractObjective:This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin – mu opioid receptor (MOR) and immune-inflammatory system.Methods:The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males.Results:Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence.Conclusion:Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

Sign in / Sign up

Export Citation Format

Share Document