Pharmacological characterization of KT-90 using cloned μ-, δ- and κ-opioid receptors

Katsumata, Seishi; Ienaga, Yuka; Minami, Masabumi; Nakagawa, Takayuki; Kanematsu, Ken; Satoh, Masamichi

doi:10.1016/0014-2999(96)00469-4

Cited by 8 publications

(1 citation statement)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…U-69,593 potencies ranked from 3 to 8 nM with 191 nM in the kappa-β-arrestin 2 interaction assay, demonstrating a robust bias towards G protein activation. Literature data showed similar potency values in receptor binding assay of 4 nM, and forskolin stimulated inhibition of cAMP of 17 nM ( Katsumata et al, 1996 ). However, G protein-biased behavior of U-69,593 is not corroborated by literature findings.…”

Section: Discussionmentioning

confidence: 77%

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

et al. 2022

View full text Add to dashboard Cite

The present study investigated the in vitro pharmacology of the human kappa opioid receptor using multiple assays, including calcium mobilization in cells expressing chimeric G proteins, the dynamic mass redistribution (DMR) label-free assay, and a bioluminescence resonance energy transfer (BRET) assay that allows measurement of receptor interaction with G protein and β-arrestin 2. In all assays, dynorphin A, U-69,593, and [D-Pro10]dyn(1-11)-NH2 behaved as full agonists with the following rank order of potency [D-Pro10]dyn(1-11)-NH2 > dynorphin A ≥ U-69,593. [Dmt1,Tic2]dyn(1-11)-NH2 behaved as a moderate potency pure antagonist in the kappa-β-arrestin 2 interaction assay and as low efficacy partial agonist in the other assays. Norbinaltorphimine acted as a highly potent and pure antagonist in all assays except kappa-G protein interaction, where it displayed efficacy as an inverse agonist. The pharmacological actions of novel kappa ligands, namely the dynorphin A tetrameric derivative PWT2-Dyn A and the palmitoylated derivative Dyn A-palmitic, were also investigated. PWT2-Dyn A and Dyn A-palmitic mimicked dynorphin A effects in all assays showing similar maximal effects but 3–10 fold lower potency. In conclusion, in the present study, multiple in vitro assays for the kappa receptor have been set up and pharmacologically validated. In addition, PWT2-Dyn A and Dyn A-palmitic were characterized as potent full agonists; these compounds are worthy of further investigation in vivo for those conditions in which the activation of the kappa opioid receptor elicits beneficial effects e.g. pain and pruritus.

show abstract

Section: Discussionmentioning

confidence: 77%

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

et al. 2022

View full text Add to dashboard Cite

show abstract

Opioids in Preclinical and Clinical Trials

Nagase

Fujii

2010

Topics in Current Chemistry

View full text Add to dashboard Cite

Pharmacological characterization of the ameliorating effect on short-term memory impairment and antinociceptive effect of KT-90 in mice

Hiramatsu¹,

Hoshino²,

Kanematsu³

2005

Behavioural Brain Research

View full text Add to dashboard Cite

(-)-3-Acetyl-6beta-acetylthio-N-cyclopropylmethyl-normorphine (KT-90) is a synthesized compound that binds to mu-, delta- and kappa-opioid receptors in vitro. KT-90 induces analgesia in the tail-flick test and this effect is antagonized by nor-BNI, a selective kappa-opioid receptor antagonist. However, lower doses of KT-90 antagonize morphine-induced analgesia. We reported that kappa-opioid receptor agonists such as U-50,488H and dynorphin A (1-13), improved scopolamine-induced impairment of learning and memory in mice and/or rats. In this study, the effects of KT-90 were investigated in an acetic acid-induced writhing test and scopolamine-induced memory impairment test using spontaneous alternation performance in a Y-maze. Male ddY mice were treated with scopolamine (1.65 micromol/kg, s.c.) 30 min before the behavioral test. KT-90 (0.07-2.35 micromol/kg, s.c.) was injected 30 min before testing. In the writhing test, the antinociceptive effect of KT-90 (0.71 micromol/kg) was completely antagonized by a selective mu-opioid receptor antagonist, beta-funaltrexamine (10.2 nmol/mouse, i.c.v.) and partially antagonized by nor-BNI (4.9 nmol/mouse, i.c.v.), but it was not antagonized by a selective delta-opioid receptor antagonist, naltrindole (9.1 pmol/mouse, i.c.v.). KT-90 significantly improved the impairment of spontaneous alternation induced by scopolamine. The ameliorating effect of KT-90 was not antagonized by nor-BNI, but was almost completely antagonized by a selective sigma receptor antagonist, NE-100 (2.6 micromol/kg, i.p.). These results suggested that the KT-90-induced antinociceptive effect was mediated by mu- and partially by kappa-opioid receptors, and the KT-90-induced improvement in scopolamine-induced impairment of spontaneous alternation was mediated mainly via sigma receptors.

show abstract

Pharmacological characterization of KT-90 using cloned μ-, δ- and κ-opioid receptors

Cited by 8 publications

References 21 publications

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

Pharmacology of Kappa Opioid Receptors: Novel Assays and Ligands

Opioids in Preclinical and Clinical Trials

Pharmacological characterization of the ameliorating effect on short-term memory impairment and antinociceptive effect of KT-90 in mice

Contact Info

Product

Resources

About