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The lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation

An effective treatment and compound technology, applied in the direction of biological testing, material inspection products, etc.

Inactive Publication Date: 2007-01-10
ACADIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, no evidence has been provided to conclusively support a role for the FPRL1 receptor in inflammatory responses in vivo

Method used

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  • The lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation
  • The lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation
  • The lipoxin receptor, FPRL1, as a tool for identifying compounds effective in the treatment of pain and inflammation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0258] Example 1: Analysis of Receptor Selection and Amplification Techniques

[0259] Functional receptor analysis, receptor selection and amplification technology (R-SAT) was used to investigate the pharmacological properties of known or novel FPRL1 agonists. R-SAT is disclosed in US Patent Nos. 5,707,798, 5,912,132 and 5,955,281, all of which are hereby incorporated by reference in their entirety (including any drawings).

[0260] Briefly, NIH 3T3 cells were grown to 70-80% confluency in 96-well tissue culture plates, and cells were transfected with plasmid DNAs for 16-20 hours using Polyfect (Qiagen Inc.) according to each manufacturer's instructions. R-SATs are typically performed with 3ng of receptor and 20ng of β-galactosidase plasmid DNA per well. All receptor and G-protein constructs used were in pSI-derived mammalian expression vectors (Promega Inc) as previously described. The FPRL1 receptor gene was amplified from genomic DNA by PCR using oligodeoxynucleoside pri...

Embodiment 2

[0264] Example 2: FPRL1 receptor binding assay

[0265] The ability of the compounds disclosed herein to bind the FPRL1 receptor can be readily determined in receptor binding assays using the following reagents, supplies and methods.

[0266] 1. COS cells transfected with FPRL1 receptor (or replaced by another transfected cell line that cannot endogenously express FPRL1 receptor) were grown in a suitable medium on a 24-well culture plate.

[0267] 2. Prepare radiolabeled assay solution, which is 245 μl, 0.25 nM [ 125 I] WKYMVm working solution was mixed with 5 μl of the following solutions (each solution): 50 μM unlabeled WKYMVm working solution, 0.25 nM [ 125 I] WKYMVm working solution, HEPES buffer alone or 50X test compound.

[0268] 3. Aspirate the medium from the 24-well plate with a Pasteur pipette connected to a vacuum. Cells were not rinsed.

[0269] 4. Add 250 μl of the radioactivity assay solution prepared in step 2 to each assay well, and place the plate on an o...

Embodiment 3

[0273] Example 3: Detection of changes in cytosolic calcium in transfected HL-60 cells

[0274] 1. Wash the HL-60 cells transfected with FPRL1 or a kind of control receptor with phosphate-buffered salt, the concentration of the HL-60 cells is 1-3×10 per milliliter 6 cells.

[0275] 2. 2 [mu]M Fura-2 was added to the cells and the increase in intracellular calcium was measured in the presence or absence of variable concentrations of the compound.

[0276] 3. At 100 nM, the response was compared to that generated by application of the standard reference ligand WKYMVm.

[0277] 4. The intracellular free calcium concentration is calculated by the following formula:

[0278] [ Ca 2 + ] 1 = K d ( F - ...

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Abstract

Disclosed herein are compounds that selectively activate the FPRL1 receptor. Further disclosed are methods of alleviating inflammatory responses by regulating key steps in leukocyte trafficking and preventing neutrophil-mediated tissue damage by administering to a subject a therapeutically effective amount of the compounds disclosed herein. In addition, methods of modulating, or specifically agonizing, the FPRL1 receptor by administering an effective amount of the compounds disclosed herein are provided.

Description

field of invention [0001] Aspects of the invention described below relate to the lipoxin receptor FPRL1 as a tool for identifying compounds effective in the treatment of pain and inflammation. The tool can be used to screen compounds but is not limited to applications for this purpose. In particular, compounds identified that are active at this receptor would be effective therapeutics that attenuate the symptoms of the immune response caused by the activation of neutrophils that lead to vascular Systolic disease, inflammation, myelosuppressive disease, cardiovascular disease, gastrointestinal disease and pain associated with these diseases. Additionally, compounds identified that are active at this receptor would be effective therapeutics administered prior to inflammatory insults that lead to activation of neutrophils leading to vasoconstrictive disease, inflammation, myelosuppressive disease , cardiovascular disease, gastrointestinal disease, and pain associated with these...

Claims

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Application Information

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IPC IPC(8): G01N33/50
Inventor 诺曼·那什奥德拉·L.·斯卡利卢斯·加戴尔罗杰·奥尔森马格那斯·古斯塔夫森
Owner ACADIA PHARMA INC
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