The Pyrazolone Originally Reported to Be a Formyl Peptide Receptor (FPR) 2/ALX–Selective Agonist Is Instead an FPR1 and FPR2/ALX Dual Agonist

Sogawa, Yoshitaka; Shimizugawa, Akiko; Ohyama, Takao; Maeda, Hiroaki; Hirahara, Kazuki

doi:10.1254/jphs.09196sc

Cited by 21 publications

(27 citation statements)

References 12 publications

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“…Compound 43 (Cpd43) is a low MW compound synthesized as an agonist for FPR2 (Burli et al, 2006) and has been shown to have this function in human leukocytes (Sogawa et al, 2009;. In vivo, Cpd43 exerts anti-inflammatory effects in murine ear inflammation and air-pouch models, which require FPR2 (Burli et al, 2006;Dufton et al, 2010;Sogawa et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Kao

Jia

et al. 2014

British J Pharmacology

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Background and PurposeAnnexin A1 (AnxA1) is an endogenous anti‐inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune‐mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast‐like synoviocytes (FLS).Experimental ApproachArthritis was induced by injection of K/BxN serum at day 0 and 2 in wild‐type (WT) or AnxA1−/− mice and clinical and histopathological manifestations measured 8–11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg−1 i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL‐induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.Key ResultsTreatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF‐α and osteoclast‐associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL‐6 secretion by mouse macrophages. In human RA joint‐derived FLS and monocyte‐derived macrophages, Cpd43 treatment inhibited IL‐6 release, while blocking FPR2 or silencing AnxA1 increased this release.Conclusions and ImplicationsThe FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti‐inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.

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Section: Introductionmentioning

confidence: 99%

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Kao

Jia

et al. 2014

British J Pharmacology

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“…When investigated, the functional repertoire triggered by small non-peptide agonists such as the Quinazolinonoe (Quin-C1) derivatives that selectively bind FPR2 [15],AG14 that selectively binds FPR1 [16], and pyrazolone that binds both receptors [17], resembles that of the pro-inflammatory peptides and not that of the anti-inflammatory agonists. Using a chemolibrary screening approach it was recently shown that agonists of FPR1/FPR2 include compounds with wide chemical diversity [18].…”

Section: Introductionmentioning

confidence: 99%

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Forsman

Kalderén

Nordin

et al. 2011

Biochemical Pharmacology

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The neutrophil formyl peptide receptors (FPR1 and FPR2) are G-protein coupled receptors that can induce pro-inflammatory as well as anti-inflammatory activities when activated. Accordingly, these receptors may become therapeutic targets for the development of novel drugs to be used for reducing the inflammation induced injuries in asthma, rheumatoid arthritis, Alzheimer's disease, cardiovascular diseases and traumatic shock. We screened a library of more then 50 K small compounds for an ability of the compounds to induce a transient rise in intracellular Ca 2+ in cells transfected to express FPR2 (earlier called FPRL1 or the lipoxin A 4 receptor). Ten agonists hits were selected for further analysis representing different chemical series and five new together with five earlier described molecules were further profiled.. Compounds 1 -10 gave rise to a calcium response in the FPR2 transfectants with EC 50 values ranging from 4 x 10 -9 M to 2 x 10 -7 M. All 10 compounds activated human neutrophils to release superoxide , and based on the potency of their activity, the three most potent activators of the neutrophil NADPH-oxidase were further characterized. These three agonists were largely resistant to inactivation by neutrophil produced reactive oxygen species and shown to trigger the same functional repertoire in neutrophils as earlier described peptide agonists. Accordingly they induced chemotaxis, granule mobilization and secretion of superoxide. Interestingly, the oxidase activity was largely inhibited by cyclosporine H, an FPR1 selective antagonist, but not by PBP10, an FPR2 selective inhibitor, suggesting that FPR1 is the preferred receptor in neutrophils for all three agonists.

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“…19 It was reported that this compound did not show significant interactions with a series of unrelated protein targets, including CXCR2 and mitogen-activated P38a kinase. 20 In addition, the compound was orally active in mice.…”

Section: Discussionmentioning

confidence: 96%

“…We previously reported that Cpd43 has agonistic activities for mouse Fpr1 and Fpr2, with 50% effective concentration (EC 50 ) values of 0Á35 and 0Á89 lM, respectively, in aequorin assays measuring calcium mobilization (Table 1 and Sogawa et al 19 ). In this study, we first investigated whether Cpd43 would induce cross-desensitization in mouse neutrophils.…”

Section: Cpd43 Induces Cross-desensitization Of Intracellular Calciummentioning

confidence: 99%

“…As Cpd43 itself induces mouse neutrophil chemotaxis with a maximal response at a concentration of 0Á1 lM, 19 we pretreated neutrophils with various concentrations of Cpd43 and washed it out before using the cells in chemotaxis assays to circumvent the effect of its chemotactic activity. Pretreatment with Cpd43 dose-dependently attenuated the chemotactic responses of mouse neutrophils to mC5a, LTB 4 or KC (Fig.…”

Section: Cpd43 Attenuates the Chemotactic Activity Of Neutrophilsmentioning

confidence: 99%

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Inhibition of neutrophil migration in mice by mouse formyl peptide receptors 1 and 2 dual agonist: indication of cross-desensitization in vivo

et al. 2010

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Summary It has been reported that the stimulation of neutrophils with N‐formyl‐Met‐Leu‐Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross‐desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non‐peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B4, or keratinocyte‐derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C‐X‐C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose‐dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound‐administered mice. The recipient mice that underwent adoptive transfer of fluorescence‐labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle‐treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross‐desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.

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The Pyrazolone Originally Reported to Be a Formyl Peptide Receptor (FPR) 2/ALX–Selective Agonist Is Instead an FPR1 and FPR2/ALX Dual Agonist

Cited by 21 publications

References 12 publications

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Inhibition of neutrophil migration in mice by mouse formyl peptide receptors 1 and 2 dual agonist: indication of cross-desensitization in vivo

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