Kappa-Opioid Receptor-Mediated Antinociceptive Effects of Stereoisomers and Derivatives of (+)-Matrine in Mice

Planta Medica ◽  
1999 ◽  
Vol 65 (3) ◽  
pp. 230-233 ◽  
Author(s):  
Ping Xiao ◽  
Hajime Kubo ◽  
Masahiro Ohsawa ◽  
Kimio Higashiyama ◽  
Hiroshi Nagase ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Antinociceptive Effects ◽  
Derivatives Of

scholarly journals Antinociceptive and Antipruritic Effects of HSK21542, a Peripherally-Restricted Kappa Opioid Receptor Agonist, in Animal Models of Pain and Itch

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Wang ◽  
Xiaoli Gou ◽  
Xiaojuan Yu ◽  
Dongdong Bai ◽  
Bowei Tan ◽  
...  
Keyword(s):  
Animal Models ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Hot Plate Test ◽  
Opioid Receptor Agonist ◽  
Antinociceptive Effects ◽  
Plasma Concentration Ratio ◽  
Cns Effects

Kappa opioid receptor (KOR) agonists have been promising therapeutic candidates, owing to their potential for relieving pain and treating intractable pruritus. Although lacking morphine-like central nervous system (CNS) effects, KOR agonists do elicit sedation, dysphoria and diuresis which seriously impede their development. Peripherally-restricted KOR agonists have a poor ability to penetrate into the CNS system, so that CNS-related adverse effects can be ameliorated or even abolished. However, the only approved peripherally-restricted KOR agonist CR845 remains some frequent CNS adverse events. In the present study, we aim to address pharmacological profiles of HSK21542, with an expectation to provide a safe and effective alternative for patients who are suffering from pain and pruritus. The in vitro experimental results showed that HSK21542 was a selective and potent KOR agonist with higher potency than CR845, and had a brain/plasma concentration ratio of 0.001, indicating its peripheral selectivity. In animal models of pain, HSK21542 significantly inhibited acetic acid-, hindpaw incision- or chronic constriction injury-induced pain-related behaviors, and the efficacy was comparable to CR845 at 15 min post-dosing. HSK21542 had a long-lasting analgesic potency with a median effective dose of 1.48 mg/kg at 24 h post-drug in writhing test. Meanwhile, the antinociceptive activity of HSK21542 was effectively reversed by a KOR antagonist nor-binaltorphimine. In addition, HSK21542 had powerful antipruritic activities in compound 48/80-induced itch model. On the other hand, HSK21542 had a weak ability to produce central antinociceptive effects in a hot-plate test and fewer effects on the locomotor activity of mice. HSK21542 didn’t affect the respiratory rate of mice. Therefore, HSK21542 might be a safe and effective KOR agonist and promising candidate for treating pain and pruritus.

scholarly journals Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene

2017 ◽  
Vol 80 (7) ◽  
pp. 2094-2100 ◽  
Author(s):  
Anil Yilmaz ◽  
Rachel Saylor Crowley ◽  
Alexander M. Sherwood ◽  
Thomas E. Prisinzano
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Receptor Activity ◽  
Kappa Opioid ◽  
Derivatives Of

scholarly journals Evaluation of Antinociceptive Effects of Chitosan-Coated Liposomes Entrapping the Selective Kappa Opioid Receptor Agonist U50,488 in Mice

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 138
Author(s):  
Liliana Mititelu Tartau ◽  
Maria Bogdan ◽  
Beatrice Rozalina Buca ◽  
Ana Maria Pauna ◽  
Cosmin Gabriel Tartau ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Kappa Opioid Receptor ◽  
Tail Flick ◽  
Opioid Agonist ◽  
Kappa Opioid ◽  
Tail Flick Test ◽  
Writhing Test ◽  
Opioid Receptor Agonist ◽  
Antinociceptive Effects

Background and Objectives: The selective kappa opioid receptor agonist U50,488 was reported to have analgesic, cough suppressant, diuretic and other beneficial properties. The aim of our study was to analyze the effects of some original chitosan-coated liposomes entrapping U50,488 in somatic and visceral nociceptive sensitivity in mice. Materials and Methods: The influence on the somatic pain was assessed using a tail flick test by counting the tail reactivity to thermal noxious stimulation. The nociceptive visceral estimation was performed using the writhing test in order to evaluate the behavioral manifestations occurring as a reaction to the chemical noxious peritoneal irritation with 0.6% acetic acid (10 mL/kbw). The animals were treated orally, at the same time, with a single dose of: distilled water 0.1 mL/10 gbw; 50 mg/kbw U50,488; 50 mg/kbw U50,488 entrapped in chitosan-coated liposomes, according to the group they were randomly assigned. Results: The use of chitosan-coated liposomesas carriers for U50,488 induced antinociceptive effects that began to manifest after 2 h, andwere prolonged but with a lower intensity than those caused by the free selective kappa opioid in both tests. Conclusion: In this experimental model, the oral administration of nanovesicles containing the selective kappa opioid agonist U50,488 determined a prolonged analgesic outcome in the tail flick test, as well as in the writhing test.

EXPERIMENTAL EVALUATION OF TOXICOMETRIC INDICATORS AND ANALGESIC ACTIVITY OF KAPPA-OPIOID RECEPTOR AGONISTS

2020 ◽  
pp. 27-33
Author(s):  
S. V. Chepur ◽  
S. E. Galan ◽  
M. S. Vakhviayanen ◽  
R. N. Khromov ◽  
A. N. Semenov
Keyword(s):  
Opioid Receptor ◽  
Analgesic Activity ◽  
Phenyl Ring ◽  
Carbon Chain ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Receptor Agonists ◽  
Piperazine Derivatives ◽  
Opioid Receptor Agonists ◽  
Derivatives Of

Data on the biological activity of kappa-opioid receptor agonists - derivatives of three groups of compounds: 1,2-cyclohexylamine, 1,2,3,4-piperidine, 1,2,4-piperazine are presented. On the examples of 1,2-cyclohexylamine and 1,2,4-piperazine derivatives, it has been shown that a decrease in the length of the carbon chain in the phenylalkyl substituent at the nitrogen atom is accompanied by a decrease in the analgesic activity and toxicity of compounds. The replacement of chlorine atoms in the 3 and 4 positions of the phenyl ring with fluorine atoms, which are more electronegative, leads to an increase in the analgesic effect and a decrease in the toxicity of the compounds.

Molecular recognition at kappa opioid receptors

2001 ◽  
Vol 73 (9) ◽  
pp. 1387-1391 ◽  
Author(s):  
Philip S. Portoghese
Keyword(s):  
Molecular Recognition ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Kappa Opioid ◽  
Molecular Modification ◽  
Opioid Receptor Antagonists ◽  
Membrane Bound ◽  
Derivatives Of

Structure­activity relationships are rarely straightforward, and often are more complicated than they appear. For this reason, the use of site-directed mutagenesis as a complementary tool to analyze structure­activity relationships has been invaluable. Here, we illustrate how site-directed mutagenesis has led to greater insight into the molecular basis for molecular recognition of norbinaltorphimine and to the design of novel kappa antagonists. Given the paucity of high-resolution crystal structures for membrane-bound receptors, the use of a coordinated "two-dimensional" paradigm that involves molecular modification of both the ligand and the receptor, affords a useful approach to the study of molecular recognition. This paradigm has led to the design of highly potent and selective kappa opioid receptor antagonists that are derivatives of the delta opioid receptor antagonist, naltrindole.

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