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Inhibitors of agonist-specific desensitization

a desensitization and agonist technology, applied in the field of desensitization, can solve the problems of loss of receptor responsiveness to subsequent stimulation, and none of the compounds utilized in these studies directly inhibit the .beta.ar kinas

Inactive Publication Date: 2004-02-26
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a method of inhibiting desensitization, a process where a cell becomes less responsive to a particular compound over time. This method involves blocking the phosphorylation of a receptor by a protein kinase, which can lead to desensitization. The invention also provides compounds that can inhibit desensitization and pharmaceutical compositions containing these compounds. The technical effect of the invention is to enhance the efficacy and duration of treatment with drugs and reduce side effects, as well as restore the effectiveness of receptor-mediated responses to endogenous compounds.

Problems solved by technology

Occupancy of a wide variety of hormone and neurotransmitter receptors by agonists often leads to desensitization, that is, to a loss of receptor responsiveness to subsequent stimulation by agonist.
Moreover, none of the compounds utilized in these studies directly inhibit the .beta.AR kinase.

Method used

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  • Inhibitors of agonist-specific desensitization

Examples

Experimental program
Comparison scheme
Effect test

example ii

Inhibition of .beta.AR Kinase Prevents Rapid Homologous Desensitization of .beta..sub.2-ARs

[0053] [.alpha.-.sup.32P]ATP, [.gamma.-.sup.32P]ATP, [3H]cAMP, .sup.125I-labeled cyanopindolol (.sup.125I-cyanopindolol), and .sup.125I-cyanopindolol diazirine were obtained from New England Nuclear; heparin (H-3125 from porcine mucosa), from Sigma. 1-5(isoquinoline sulfonyl)-2-methylpiperazine (designated H-7), from Calbiochem; and digitonin, from Gallard Schlessinger. The peptide corresponding to residues 1-24 of the heat-stable inhibitor of cAMP-dependent protein kinase [PKI-(1-24) tetracosapeptide: Scott et al Proc. Natl. Acad. Sci. USA (1986) 83:1613-1616] and the .beta..sub.2AR-(57-71) pentadecapeptide (Ala-Ile-Ala-Lys-Phe-Glu-Arg-Leu-Gln-Thr-Val-Thr-Asn-Tyr-Phe; Kobilka et al Proc. Natl. Acad. Sci USA (1987) 84:46-50) and .beta..sub.2AR-(59-69) undecapeptide (Ala-Lys-Phe-Glu-Arg-Leu-Gln-Thr-Val-Thr-Asn) were chemically synthesized.

[0054] Purified .beta..sub.2AR was phosphorylated by pur...

example iii

Synthetic Peptides of the Hamster .beta..sub.2AR as Substrates and Inhibitors of the .beta.AR Kinase

[0070] Peptides were synthesized by tBOC chemistry on an Applied Biosystems 430A Synthesizer. Peptides were deblocked by HF treatment and were purified by reverse phase high performance liquid chromatography on a C18 column using a 0-50% acetonitrile gradient.

[0071] The .beta.2-adrenergic receptor from hamster lung was purified to apparent homogeneity by sequential affinity and high performance liquid chromatography as described (Benovic et al (1984) Biochemistry 23:4510-4518). The purified receptor was reinserted into phosphatidylcholine vesicles as previously described (Cerione et al (1983) Nature 306:562-566). The protein-lipid pellets were resuspended in 20 mM Tris-HCl, pH 7.2, 2 mM EDTA and used as a substrate for the .beta.AR kinase.

[0072] .beta.AR kinase was purified from bovine cerebral cortex by modification of a previously described procedure (Benovic et al (1987) J. Biol. C...

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Abstract

The present invention relates to a method of inhibiting desensitization of a cell to the effects of a compound. The method comprises contacting the cell with an agent capable of inhibiting phosphorylation, by a protein kinase, of a receptor for the compound present on the surface of the cell. The present invention also relates to a method of screening a compound for its ability to inhibit desensitization. The method comprises: i) contacting a receptor specific kinase-containing sample with the compound under conditions such that interaction between receptor specific kinase present in the sample and the compound can occur, and ii) determining the ability of the receptor specific kinase to phosphorylate the receptor for which it is specific.

Description

[0001] 1. Technical Field[0002] The present invention relates, in general, to desensitization, and, in particular, to a method of inhibiting agonist-specific desensitization, to compounds suitable for use in such a method and to pharmaceutical compositions comprising same.[0003] 2. Background Information[0004] Desensitization is a general phenomenon which is characterized by a reduced responsiveness following prolonged exposure to a hormone or drug. Occupancy of a wide variety of hormone and neurotransmitter receptors by agonists often leads to desensitization, that is, to a loss of receptor responsiveness to subsequent stimulation by agonist. This particular phenomenon is generally termed homologous desensitization. This is in contrast to the heterologous form of desensitization, which is defined as a loss of receptor responsiveness caused by agonist occupancy of other receptors.[0005] Homologous desensitization has been most thoroughly studied for the .beta.-adrenergic receptor (....

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/21A61K31/66A61K31/675A61K38/16A61K38/17G01N33/566G01N33/573
CPCA61K31/21A61K31/66A61K31/675A61K38/1787G01N33/566G01N33/573A61K31/715
Inventor LEFKOWITZ, ROBERT J.LOHSE, MARTIN J.BENOVIC, JEFFREY L.CARON, MARC G.
Owner DUKE UNIV
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