Screening methods using g-protein coupled receptors and related compositions
AssigneesChugai Pharmaceutical Co., Ltd., The General Hospital Corporation
InventorsThomas J. GARDELLA, John T. Potts, JR., Masaru Shimizu, Fumihiko Ichikawa, Harald Jüppner, Makoto Okazaki
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Abstract
The present invention provides screening methods for GPCRs based on the discovery that the affinity of a receptor agonist for a GPCR (such as the parathyroid hormone receptor) when not bound to a G-protein is correlated with the length of time over which the agonist is effective, independently of its pharmacokinetic properties. The invention also provides PTH- and PTHrP-derived polypeptides.
Claims32
A method for determining whether a candidate compound is a long-acting agonist of a G protein coupled receptor (GPCR), said method comprising:
- (a) contacting said GPCR with said compound, wherein said GPCR is in the RG form;
- (b) measuring the affinity of said compound for the RG form of said GPCR;
- (c) contacting said GPCR with said compound, wherein said GPCR is in the R0 form;
- and
- (d) measuring the affinity of said compound for the R0 form of said GPCR, wherein a compound that (i) that has an affinity for the RG form of said GPCR that is at least 10% of an endogenous agonist for said GPCR, and (ii) has a greater affinity for the R0 form of said GPCR than said endogenous agonist is identified as a long-acting agonist of said GPCR.
A method for determining whether a candidate compound is a short-acting agonist of a G protein coupled receptor (GPCR), said method comprising:
- (a) contacting said GPCR with said compound, wherein said GPCR is in the RG form;
- (b) measuring the affinity of said compound for the RG form of said GPCR;
- (c) contacting said GPCR with said compound, wherein said GPCR is in the R0 form;
- and
- (d) measuring the affinity of said compound for the R0 form of said GPCR, wherein a compound that (i) that has an affinity for the RG form of said GPCR that is at least 10% of an endogenous agonist for said GPCR, and (ii) has a lower affinity for the R0 form of said GPCR than said endogenous agonist is identified as a short-acting agonist of said GPCR.
Dependencies are inferred from the claim text.