Human G Protein-Coupled Receptors and Modulators Thereof for the Treatment of Metabolic-Related Disorders

Abstract

The present invention relates to methods of identifying whether a candidate compound is a modulator of a G protein-coupled receptor (GPCR). In preferred embodiments, the GPCR is human. In other preferred embodiments, the GPCR is coupled to Gi and lowers the level of intracellular cAMP. In other preferred embodiments, the GPCR is expressed endogenously by adipocytes. In further preferred embodiments, the GPCR inhibits intracellular lipolysis. In other further preferred embodiments, the GPCR is a nicotinic acid receptor. The present invention also relates to methods of using a modulator of said GPCR. Preferred modulator is agonist. Agonists of the invention are useful as therapeutic agents for the prevention or treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, stroke, insulin resistance, and type 2 diabetes.

1 . A method of identifying whether a candidate compound is a modulator of a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
 (a) SEQ. ID. NO.:36 (hRUP25);   (b) SEQ. ID. NO.:137(mRUP25); and   (c) SEQ. ID. NO.: 139 (rRUP25);   or an allelic variant, a biologically active mutant, or a biologically active fragment of said amino acid sequence;   comprising the steps of:   (a′) contacting the candidate compound with the receptor; and   (b′) determining whether the receptor functionality is modulated;   wherein a change in receptor functionality is indicative of the candidate compound being a modulator of a nicotinic acid GPCR.   
     
     
         2 - 11 . (canceled) 
     
     
         12 . A method of identifying whether a candidate compound binds to a nicotinic acid GPCR, said receptor comprising an amino acid sequence selected from the group consisting of:
 (a) SEQ. ID. NO.:36 (hRUP25);   (b) SEQ. ID. NO.: 137 (mRUP25); and   (c) SEQ. ID. NO.:139 (rRUP25);   or an allelic variant or a biologically active fragment of said amino acid sequence;   comprising the steps of:   (a′) contacting the receptor with a labeled reference compound known to bind to the GPCR in the presence or absence of the candidate compound; and   (b′) determining whether the binding of said labeled reference compound to the receptor is inhibited in the presence of the candidate compound;   wherein said inhibition is indicative of the candidate compound binding to a nicotinic acid GPCR.   
     
     
         13 - 41 . (canceled)