New ‘chemical probes’ to examine the role of the hFPRL1 (or ALXR) receptor in inflammation

Frohn, Mike; Xu, Han; Zou, Xiaoming; Chang, Catherine; McElvaine, Michele; Plant, Matthew; Wong, Min‐Liang; Tagari, Philip; Hungate, Randall W.; Bürli, Roland W.

doi:10.1016/j.bmcl.2007.09.043

Cited by 31 publications

(45 citation statements)

References 30 publications

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“…Compound 1 and 2 in this study (Fig 1) are enantiomers of an earlier described FPR2 agonist (Acadia C7; http://www.wipo.int/pctdb/en/wo.jsp?wo=2005047899), that has been shown to dose dependently prevent hyperalgesia induced by carrageenan in a rat model. It should be noticed that large differences have been described for receptor agonists and their enantiomers [41], but in our hands compound 1 and 2 were equally potent, but not among the most potent neutrophil activators in. Compound 3 used in this study is a substituted quinazinolione (QuinC1), that has been described to be chemotactic and induce degranulation in neutrophils [42], but be unable to stimulate superoxide production [15].…”

Section: Discussioncontrasting

confidence: 46%

“…The described non-peptide ligands for FPR1 and 2 may also serve as the nucleus for further structural modifications leading to the discovery of more potent and efficacious agonists. This type of work has been performed 21 already, using the pyrazolone originally described as an FPR2 agonist, and an even more potent FPR2 agonist has been described together with a 100 fold less active enatiomer [41].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

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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“…Thus, we rescreened a subset of this compound library for novel FPR1/FPR2 agonists using a Ca 2ϩ mobilization assay. The subset of 6000 compounds was selected from the parent library as compounds that contained at least two heterocycles separated by a chemical linker with Ͼ2 bonds, because previous studies have shown that these characteristics are almost always present in nonpeptide FPR1/FPR2 agonists (Nanamori et al, 2004;Edwards et al, 2005;Bü rli et al, 2006;Frohn et al, 2007;Schepetkin et al, 2007Schepetkin et al, , 2008Zhou et al, 2007). To distinguish between FPR1 and FPR2 agonists, we performed primary high-throughput screening for compounds that activated Ca 2ϩ mobilization in RBL cell lines transfected with either human FPR1 or FPR2.…”

Section: Resultsmentioning

confidence: 99%

“…For development of the FPR1 ligand-binding site template, we chose 1910-5441 (Edwards et al, 2005) and AG-14 (Schepetkin et al, 2008), two previously reported FPR1 agonists, and AG-09/2. Two previously reported FPR2 agonists, Bü rli-25 (Bü rli et al, 2006) and Frohn-11 (Frohn et al, 2007), and three agonists identified here (AG-09/5, AG-09/74, and AG-26) were selected for development of the FPR2 ligand-binding site template. Using the conformer hunt algorithm (FieldTemplater Version 2.0.1), we generated up to 100 independent conformations lying within 6-kcal/mol energy gap above the lowestenergy geometry for each of the molecules.…”

Section: Characterization Of Novel Fpr1/fpr2 Agonists 165mentioning

confidence: 99%

Identification of Novel Small-Molecule Agonists for Human Formyl Peptide Receptors and Pharmacophore Models of Their Recognition

Kirpotina

Khlebnikov²,

Schepetkin

et al. 2009

Mol Pharmacol

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N-formyl peptide receptor (FPR1) and N-formyl peptide receptor-like 1 (FPRL1, now known as FPR2) are G protein-coupled receptors involved in host defense and sensing cellular dysfunction. Because of the potential for FPR1/FPR2 as a therapeutic target, our recent high-throughput screening efforts have focused on the identification of unique nonpeptide agonists of FPR1/FPR2. In the present studies, we screened a chemolibrary of drug-like molecules for their ability to induce intracellular calcium mobilization in RBL-2H3 cells transfected with human FPR1 or FPR2. Screening of these compounds resulted in the identification of novel and potent agonists that activated both FPR1 and FPR2, as well as compounds that were specific for either FPR1 or FPR2 with EC 50 values in the low micromolar range. Specificity of the compounds was supported by analysis of calcium mobilization in HL-60 cells transfected with human FPR1 and FPR2. In addition, all but one agonist activated intracellular calcium flux and chemotaxis in human neutrophils, irrespective of agonist specificity for FPR1 or FPR2. Molecular modeling of the group of FPR1 and FPR2 agonists using field point methodology allowed us to create pharmacophore models for ligand binding sites and formulate requirements for these specific N-formyl peptide receptor agonists. These studies further demonstrate that agonists of FPR1/ FPR2 include compounds with wide chemical diversity and that analysis of such compounds can enhance our understanding of their ligand/receptor interaction.

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“…Five agonists with known enantiomeric configurations and relatively high activity at FPR2 were chosen for pharmacophore modeling. The selected structures included PD168368, AG-10/5, AG-10/8, AG-10/17, and compound 11 from (Frohn et al, 2007) [1-((5-methoxyindol-2-yl)carbonyl)-3-(2-ethylbenzimidazol-1-yl)(3R)pyrrolidine; designated here as . We used a ligand-based approach for molecular modeling based on the use of field points (Cheeseright et al, 2007), as described in our previous studies (Kirpotina et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

et al. 2010

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N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in host defense and sensing cellular dysfunction. Thus, FPRs represent important therapeutic targets. In the present studies, we screened 32 ligands (agonists and antagonists) of unrelated GPCRs for their ability to induce intracellular Ca 2ϩ mobilization in human neutrophils and HL-60 cells transfected with human FPR1, FPR2, or FPR3. Screening of these compounds demonstrated that antagonists of gastrin-releasing peptide/neuromedin B receptors ( -(4-nitrophenyl) Phe-based PD176252/PD168368 analogs and 41 related nonpeptide/nonpeptoid analogs revealed 22 additional FPR agonists. Most were potent mixed FPR1/FPR2/FPR3 agonists with nanomolar EC 50 values for FPR2, making them among the most potent nonpeptide FPR2 agonists reported to date. In addition, these agonists were also potent chemoattractants for murine and human neutrophils and activated reactive oxygen species production in human neutrophils. Molecular modeling of the selected agonists using field point methods allowed us to modify our previously reported pharmacophore model for the FPR2 ligand binding site. This model suggests the existence of three hydrophobic/aromatic subpockets and several binding poses of FPR2 agonists in the transmembrane region of this receptor. These studies demonstrate that FPR agonists could include ligands of unrelated GPCR and that analysis of such compounds can enhance our understanding of pharmacological effects of these ligands.

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New ‘chemical probes’ to examine the role of the hFPRL1 (or ALXR) receptor in inflammation

Cited by 31 publications

References 30 publications

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

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

Identification of Novel Small-Molecule Agonists for Human Formyl Peptide Receptors and Pharmacophore Models of Their Recognition

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

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