G-protein coupled receptors (GPCRs) constitute a major class of proteins responsible for transducing a signal within a cell. Upon binding of a ligand to an extracellular portion of a GPCR, a signal is transduced within the cell that results in a change in a biological or physiological property of the cell. GPCRs, along with G-proteins and effectors (intracellular enzymes and channels modulated by G-proteins), are the components of a modular signaling system that connects the state of intracellular second messengers to extracellular inputs.
GPCR genes and gene-products are potential causative agents of disease (Spiegel et al., J. Clin. Invest. 92:1119 1125 (1993)). For example, specific defects in the rhodopsin gene and the V2 vasopressin receptor gene have been shown to cause various forms of retinitis pigmentosum (Nathans et al., Annu. Rev. Genet. 26:403 424 (1992)), and nephrogenic diabetes insipidus (Holtzman et al., Hum. Mol. Genet. 2:1201 1204 (1993)). These receptors are important to both the central nervous system and peripheral physiological processes.
G protein coupled receptor 120 (GPR120) is an orphan G protein-coupled receptor that is abundantly expressed in intestine, and functions as a receptor for unsaturated long-chain free fatty acids (FFAs). (Hirasawa et al., Nature Medicine 11:90-94 (2005)). Stimulation of GPR120 by FFAs has been reported to promote the secretion of glucagon-like peptide-1 (GLP-1) and increase circulating insulin, and to activate the extracellular signal-regulated kinase (ERK) cascade. (Katsuma et al., J. Biol. Chem. 280:19507-19515 (2005)). Peripherally, GLP-1 affects gut motility, and inhibits gastric acid and glucagon secretion. In the central nervous system, GLP-1 induces satiety, leading to reduced weight gain. In the pancreas, GLP-1 induces expansion of insulin-secreting β-cell mass, in addition to the augmentation of glucose-stimulated insulin secretion. (MacDonald et al., Diabetes 51:Supp. 3 S434-S442 (2002)).
Given the significance of GLP-1 as a potent insulinotropic incretin and in appetite and feeding control, GPR120 is a promising target for the treatment of diabetes, obesity and other eating disorders. Because of the importance of GPCRs as targets for drug action and development, there remains a need for the development of agents which modulate GPCR function.