Non-endogenous, constitutively activated human serotonin receptors and small molecule modulators thereof

• US 6,541,209 B1
• Filed: 04/14/1999
• Issued: 04/01/2003
• Est. Priority Date: 04/14/1997
• Status: Expired due to Term

• Current Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Arena Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Thomsen, William J., Russo, Joseph F., Liaw, Chen W., Chalmers, Derek T., Behan, Dominic P.
• Primary Examiner(s): Eyler, Yvonne
• Assistant Examiner(s): BASI, NIRMAL SINGH
• Application Number:
  US09/292,072
• Time in Patent Office: 1,448 Days
• Field of Search: 435/7.1, 435/69.1, 435/325, 435/172.3, 435/252.3, 536/24.3, 536/23.1, 530/300, 530/350
• 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 14/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: C07K 14/723 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
• CPC Class Codes: G01N 2333/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

Disclosed herein are non-endogenous, constitutively activated forms of the human 5-HT_2A and human 5-HT_2C receptors and uses of such receptors to screen candidate compounds. Further disclosed herein are candidate compounds identified by the screening method which act at the 5HT_2A receptors. Yet further disclosed is a new class of compounds which act at the 5HT_2A receptors.

Claims

1. A method of identifying whether a candidate compound is an inverse agonist to a non-endogenous human 5HT2 serotonin receptor comprising the steps of:

a. contacting the candidate compound with a non-endogenous human 5HT2 serotonin receptor, said receptor comprising the amino acid sequence of SEQ.ID.NO.;

31; and

b. determining, by measurement of the compound efficacy at said contacted receptor whether said compound is an inverse agonist, said compound efficacy measurement being an inhibition of a second messenger response relative to a second messenger response of said receptor in the absence of said compound, said second messenger response being selected from the group consisting of levels of inositol triphosphate (IP₃) and levels of diacycglycerol (DAG).