Discovery of S-777469: An orally available CB2 agonist as an antipruritic agent

Odan, Masahide; Ishizuka, Natsuki; Hiramatsu, Yoshihiro; Inagaki, Miwako; Hashizume, Hiroshi; Fujii, Yasuhiko; Mitsumori, Susumu; Morioka, Yasuhide; Soga, Masahiko; Deguchi, Masashi; Yasui, Kiyoshi; Arimura, Akinori

doi:10.1016/j.bmcl.2012.02.072

Cited by 49 publications

(44 citation statements)

References 10 publications

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“…Recent pharmacological improvements allow oral application of specific CB-2 agonists (i.e., S-777469) and specific CB-2 antagonists/inverse agonists (i.e., SR 144528); therefore (38,39), their potential medical applications in the treatment of various diseases are becoming even more noteworthy. By contrast, safety and adverse effects of CB-2 agonists/antagonists/inverse agonists should be examined prior to clinical use.…”

Section: Discussionmentioning

confidence: 99%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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Abstract. The bone remodeling process is influenced by various factors, including estrogens and transmitters of the endocannabinoid system. In osteoblasts, cannabinoid receptors 2 (CB-2) are expressed at a much higher level compared to CB-1 receptors. Previous studies have shown that estrogens could influence CB-2 receptor expression. In the present study, the possible interactions of a specific CB-2 agonist and a specific CB-2 antagonist/inverse agonist with 17-β-estradiol were investigated in primary human osteoblasts (HOB). HOB cells were cultured in phenol red-free osteoblast growth medium (37˚C, 5% CO 2 ). In their 5th passage, HOB were exposed to different concentrations of i) 17-β-estradiol (1, 10 and 100 nM); ii) a specific CB-2 agonist (R,S)-AM1241 (1 and 7.5 µM); and iii) a specific CB-2 antagonist/inverse agonist AM630 (10 µM) and to selected combinations of the substances. After 24 and 48 h of incubation, HOB proliferation activity was measured using a WST-8 assay. Alkaline phosphatase activity was also evaluated using spectrophotometry. Concomitant exposure of HOB to 17-β-estradiol (10 nM) and to specific CB-2 antagonist/inverse agonist (10 µM) showed similar HOB proliferation activity to HOB incubated with 17-β-estradiol only at a 100 nM concentration. By contrast, concomitant incubation of HOB with 17-β-estradiol (10 nM) and specific CB-2 agonist (7.5 µM) resulted in decreased HOB proliferation activity as compared to HOB incubated with 17-β-estradiol only (10 nM). Similar findings were observed after 24 and 48 h of incubation. In all the experiments, HOB successfully passed the alkaline phosphatase differentiation test. In conclusion, for the first time a synergistic interaction between 17-β-estradiol and specific CB-2 antagonist/inverse agonist was observed in HOB. Understanding the molecular pathways of this interaction would be of great importance in developing more efficient and safer drugs for treating or preventing bone diseases.

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Section: Discussionmentioning

confidence: 99%

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

et al. 2015

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“…We previously showed that S-777469 dose-dependently inhibited compound 48/80-induced scratching behavior [19]. Here, we investigated the effects of pretreatment with SR144528, a CB 2 antagonist, to clarify whether the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior in mice are mediated by CB 2 .…”

Section: Resultsmentioning

confidence: 99%

“…These findings prompted us to explore CB 2 -selective agonists as antipruritic drugs, without side effects on the CNS mediated by CB 1 , and we discovered S-777469. In that previous study [19], we examined the in vitro activity of S-777469 for CB 1 and CB 2 and demonstrated that S-777469 is a CB 2 -selective agonist with no side effects on the CNS. In addition, the effects of S-777469 on various other receptors or enzymes were evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we tried to find novel CB 2 -selective agonists that were antipruritic agents without side effects in the CNS, and developed S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid]. In a previous paper, we demonstrated that S-777469 possessed selective binding as well as agonistic activities for CB 2 compared to CB 1 and significantly suppressed compound 48/80-induced scratching behavior in mice [19]. …”

Section: Introductionmentioning

confidence: 99%

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S-777469, a Novel Cannabinoid Type 2 Receptor Agonist, Suppresses Itch-Associated Scratching Behavior in Rodents through Inhibition of Itch Signal Transmission

Haruna¹,

Soga

Morioka

et al. 2015

Pharmacology

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We have previously reported that S-777469 [1-([6-ethyl-1-(4-fluorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl]amino)-cyclohexanecarboxylic acid], a novel cannabinoid type 2 receptor (CB₂) agonist, significantly suppressed compound 48/80-induced scratching behavior in mice in a dose-dependent manner when it was administered orally. Here, we demonstrated that the inhibitory effects of S-777469 on compound 48/80-induced scratching behavior are reversed by pretreatment with SR144528, a CB₂-selective antagonist. In addition, we investigated the effects of S-777469 on itch-associated scratching behavior induced by several pruritogenic agents in mice and rats. S-777469 significantly suppressed scratching behavior induced by histamine or substance P in mice or by serotonin in rats. In contrast, the H₁-antihistamine fexofenadine clearly inhibited histamine-induced scratching behavior but did not affect scratching behavior induced by substance P or serotonin. Moreover, S-777469 significantly inhibited histamine-induced peripheral nerve firing in mice. In conclusion, these results suggest that S-777469 produces its antipruritic effects by inhibiting itch signal transmission through CB₂ agonism.

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“…e method was applied to quantify S-777469 (1-((6-ethyl-1-(4-uorobenzyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carbonyl) amino)-cyclohexanecarboxylic acid), a synthetic cannabinoid receptor 2 selective agonist, 26) or raclopride (RCP), a dopamine D2 receptor selective antagonist, 27) in tissue sections from di erent mouse organs, and evaluated. …”

Section: Introductionmentioning

confidence: 99%

Quantification of Small Molecule Drugs in Biological Tissue Sections by Imaging Mass Spectrometry Using Surrogate Tissue-Based Calibration Standards

2014

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Quantitative analysis of administered drugs in biological tissues is essential for understanding the mechanisms underlying their e cacy or toxicity. Imaging mass spectrometry (IMS) may allow the quanti cation of targeted drugs in tissue sections along with the visualization of their spatial distribution. In this study, surrogate tissue-based calibration standards were prepared to quantify a small molecule drug (S-777469 or raclopride) in tissue sections of mice administered with the drug, followed by analysis with a linear ion trap mass spectrometer equipped with a matrix-assisted laser desorption/ionization (MALDI) source. e distribution of the drugs in the dissected organs was clearly visualized by MALDI-IMS. e drug concentration determined using the calibration standards prepared for MALDI-IMS analysis was highly consistent with that determined by liquid chromatography-tandem mass spectrometry, and the quanti cation in multiple organs was enabled. e results of this study show that MALDI-IMS can be used to quantify small molecule drugs in biological tissue sections using surrogate tissue-based calibration standards.

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Discovery of S-777469: An orally available CB2 agonist as an antipruritic agent

Cited by 49 publications

References 10 publications

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

A synergistic interaction of 17-β-estradiol with specific cannabinoid receptor type 2 antagonist/inverse agonist on proliferation activity in primary human osteoblasts

S-777469, a Novel Cannabinoid Type 2 Receptor Agonist, Suppresses Itch-Associated Scratching Behavior in Rodents through Inhibition of Itch Signal Transmission

Quantification of Small Molecule Drugs in Biological Tissue Sections by Imaging Mass Spectrometry Using Surrogate Tissue-Based Calibration Standards

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