Endogenous constitutively activated G protein-coupled orphan receptors

• US 6,653,086 B1
• Filed: 07/30/1999
• Issued: 11/25/2003
• Est. Priority Date: 04/14/1998
• Status: Expired due to Term

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Lowitz, Kevin P., Lin-Lin, I, Liaw, Chen W., Chen, Ruoping, Chalmers, Derek T., Behan, Dominic P.
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): BASI, NIRMAL SINGH
• Application Number:
  US09/364,425
• Time in Patent Office: 1,579 Days
• Field of Search: 435/7.1, 435/7.2, 435/7.21, 435/69.1, 435/70.1, 435/320.1, 435/172.3, 530/300, 530/350, 536/23.1, 424/192.1
• US Class Current: 435/7.1
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 233/42 Sulfur atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07K 14/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/68 involving proteins, peptides or amino acids involving lipoproteins G01N33/92

Abstract

Disclosed herein are techniques for directly identifying candidate compounds as agonists, partial agonists and/or, most preferably, inverse agonists, to endogenous, constitutively activated orphan G protein-coupled receptors. Such directly identified compounds can be utilized, most preferably, in pharmaceutical compositions

Claims

1. A method for identifying one or more compounds as an agonist or inverse agonist of an endogenous, constitutively active G protein coupled cell surface receptor, wherein the endogenous ligand for said receptor has not been identified, comprising the steps of:

(a) providing a GPCR Fusion Protein, said GPCR Fusion Protein comprising;

(i) an endogenous, constitutively active G protein coupled cell surface receptor, wherein the endogenous ligand for said receptor has not been identified; and

(ii) a Gsα

protein;

(b) contacting said GPCR Fusion Protein with one or more candidate compounds;

(c) measuring the ability of said compound to inhibit or stimulate the activity of said receptor; and

(d) identifying one or more of said compounds to be agonist or inverse agonist of said receptor, wherein said compound is identified as an agonist by stimulating the activity of said receptor, and said inverse agonist is identified by inhibiting the activity of said receptor.

2. The method of claim 1, wherein one or more of said compounds are directly identified as an inverse agonist to said receptor.

3. The method of claim 1, wherein one or more of said compounds are directly identified as an agonist to said receptor.