Non-endogenous, constitutively activated known G protein-coupled receptors

• US 20060183164A1
• Filed: 04/14/2006
• Published: 08/17/2006
• Est. Priority Date: 04/07/2000
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Liaw, Chen W., Lin, I-Lin, Lehmann-Bruinsma, Karin
• Granted Patent: US 7,381,522 B2
• Time in Patent Office: Days
• US Class Current: 435/7.200
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 14/723 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2500/10 involving cells
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

The invention disclosed in this patent document relates to transmembrane receptors, more particularly to a human G protein-coupled receptor for which the endogenous ligand is known (“known GPCRs”), and most particularly to mutated (non-endogenous) versions of the known GPCRs for use, most preferably in screening assays for the direct identification of candidate compounds as inverse agonists, agonists and partial agonists.

Claims

1. A method for directly identifying a non-endogenous compound as a compound having an activity selected from the group consisting of:

inverse agonists, parallel agonists, and partial agonists, to a non-endogenous, constitutively activated version of known G protein-coupled receptor, said receptor comprising a transmembrane-6 region and an intracellular region, comprising the steps of;

(a) selecting a non-endogenous version of a known GPCR having an amino acid sequence selected from the group consisting of

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(b) confirming that the selected non-endogenous GPCR of step (a) is constitutively active;

(c) contacting a non-endogenous candidate compound with the non-endogenous, constitutively activated GPCR of step of (b); and

(d) determining, by measurement of the compound efficacy at said contacted receptor, whether said non-endogenous compound having inverse agonist activity as an inverse agonist or agonist activity is an agonist to said receptor of step (b).

2. The method of claim 1 further comprising the following step:

assessing, by using an endogenous ligand based assay, the impact of the non-endogenous compound of step (d) on the binding of an endogenous ligand for the known GPCR version of the non-endogenous version of said known GPCR of step (a) with said known GPCR.

3. The method of claim 2 wherein said non-endogenous compound is an allosteric modulator of said known GPCR.