Methods and compositions for reducing the development of drug tolerance and/or physical dependence
AssigneeThe Regents of the University of California
InventorsJennifer Whistler, Mark von Zastrow
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Abstract
The present invention provides methods for reducing, preventing or delaying the development of tolerance to certain drugs that target G-protein coupled receptors (GPCR). The methods are generally carried out by co-administering with the drug an agonist for the drug-target GPCR that promotes the endocytosis of the targetted receptor. The methods are particularly useful for drugs that target the opioid receptors, for example morphine. The present invention also provides compositions comprising a drug and an agonist that are advantageous in preventing the development of tolerance to the drug that can develop when the drug is administered alone.
Claims28
A pharmaceutical composition comprising:
- a drug that targets a G protein-coupled receptor (GPCR), wherein the drug does not promote endocytosis and resensitization of the targetted GPCR;
- an agonist for the GPCR, wherein the agonist promotes the endocytosis of the GPCR and is present in the composition in an amount sufficient to promote endocytosis and resensitization of the targetted GPCR;
- and
- a pharmaceutically acceptable carrier.
A method for reducing, preventing or delaying the development of tolerance to, and/or physical dependence on, a drug that targets a G protein-coupled receptor (GPCR), wherein said tolerance and/or physical dependence develops as a consequence of the failure of the drug to promote endocytosis and resensitization of the targetted GPCR, said method comprising achieving co-administration of the drug and an agonist for the GPCR in a subject by:
- administering the drug to a subject receiving the agonist;
- administering the agonist to a subject receiving the drug;
- or
- administering the drug and the agonist to a subject;
- wherein the agonist promotes the endocytosis of the GPCR and is present in the subject in an amount sufficient to promote endocytosis of the GPCR, whereby the drug-targetted GPCR is endocytosed and resensitized;
A method of screening for an agent that reduces, prevents or delays the development of tolerance to, and/or physical dependence on, a drug that targets a G protein-coupled receptor (GPCR), said method comprising:
- contacting a test agent with a cell comprising the GPCR;
- determining whether the test agent promotes the endocytosis of the GPCR;
- selecting a test agent that promotes endocytosis of the GPCR as an agent that may reduce, prevent or delay the development of tolerance to, and/or physical dependence on, the drug.
Dependencies are inferred from the claim text.