Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids

The seeds of the akuamma tree (Picralima nitida) 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 in vitro 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.

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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.v1 ◽

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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Nalbuphine, a kappa opioid receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.172702 ◽

2019 ◽

Vol 864 ◽

pp. 172702 ◽

Cited By ~ 8

Author(s):

Saadet Inan ◽

Alvaro Torres-Huerta ◽

Liselotte E. Jensen ◽

Nae J. Dun ◽

Alan Cowan

Keyword(s):

Contact Dermatitis ◽

Receptor Antagonist ◽

Opioid Receptor ◽

Receptor Agonist ◽

Mu Opioid Receptor ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Mu Opioid ◽

Opioid Receptor Antagonist ◽

Opioid Receptor Agonist

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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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Inhibition of cholinergic neurotransmission in human airways by opioids

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.3.1096 ◽

1992 ◽

Vol 72 (3) ◽

pp. 1096-1100 ◽

Cited By ~ 28

Author(s):

M. G. Belvisi ◽

C. D. Stretton ◽

G. M. Verleden ◽

S. J. Ledingham ◽

M. H. Yacoub ◽

...

Keyword(s):

Opioid Receptor ◽

Receptor Agonist ◽

Therapeutic Potential ◽

Mu Opioid Receptor ◽

Dependent Manner ◽

Mu Opioid ◽

Cholinergic Neurotransmission ◽

Opioid Receptor Agonist ◽

Human Airways

Opioids reduce the cholinergic responses to electrical field stimulation (EFS) in guinea pig and canine airways by a prejunctional effect. We determined whether a similar effect operates in human airways in vitro. [D-Ala2-NMePhe4-Gly-ol5]enkephalin (DAMGO) (10(-8)-10(-6) M), a selective mu-opioid receptor agonist, inhibited the response to EFS in a dose- and frequency-dependent manner. DAMGO (10(-6) M) produced 86% inhibition at 0.5 Hz and 38% inhibition at 4 Hz, but at 32 Hz there was no significant inhibition. Another selective mu-opioid receptor agonist H-Tyr-D-Arg-Gly-Phe(4-NO2)-Pro-NH2 diacetate (BW 443C) also inhibited responses to EFS, producing 57.7% inhibition at 4 Hz at a concentration of 10(-6) M. The inhibitory effect on EFS was blocked by the opioid receptor antagonist naloxone (10(-5) M), indicating that opioid receptors are involved. DAMGO (10(-6) M) had no effect on the contractile response to exogenous acetylcholine, indicating a prejunctional effect. We conclude that mu-opioid agonists inhibit cholinergic neurotransmission in human airways in vitro, and this could have therapeutic potential in the treatment of airway disease.

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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

Journal of Medicinal Chemistry ◽

10.1021/jm4012214 ◽

2013 ◽

Vol 56 (22) ◽

pp. 9156-9169 ◽

Cited By ~ 15

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

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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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