Research ArticlePharmacology

Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake

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Science Signaling  31 May 2016:
Vol. 9, Issue 430, pp. ra55
DOI: 10.1126/scisignal.aac8035

Discovering chemicals that control appetite

Understanding the signals that control hunger and food intake is important given the global increase in metabolic disease. The neuropeptide b-LEN and its receptor GPR171 regulate food intake in mice. Wardman et al. used structural modeling and virtual molecule docking to identify candidate chemical ligands for GPR171. One of these, MS0015203, selectively bound to GPR171 and required GPR171 to stimulate a response in cultured cells and in mice. This drug, when delivered by injection into the periphery, stimulated food intake and increased body weight in a manner dependent on GPR171. Thus, not only is this drug useful in exploring the functions of GPR171, but this study demonstrates the utility of virtual screening to identify small molecules that regulate appetite.


Several neuropeptide systems in the hypothalamus, including neuropeptide Y and agouti-related protein (AgRP), control food intake. Peptides derived from proSAAS, a precursor implicated in the regulation of body weight, also control food intake. GPR171 is a heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor (GPCR) for BigLEN (b-LEN), a peptide derived from proSAAS. To facilitate studies exploring the physiological role of GPR171, we sought to identify small-molecule ligands for this receptor by performing a virtual screen of a compound library for interaction with a homology model of GPR171. We identified MS0015203 as an agonist of GPR171 and demonstrated the selectivity of MS0015203 for GPR171 by testing the binding of this compound to 80 other membrane proteins, including family A GPCRs. Reducing the expression of GPR171 by shRNA (short hairpin RNA)–mediated knockdown blunted the cellular and tissue response to MS0015203. Peripheral injection of MS0015203 into mice increased food intake and body weight, and these responses were significantly attenuated in mice with decreased expression of GPR171 in the hypothalamus. Together, these results suggest that MS0015203 is a useful tool to probe the pharmacological and functional properties of GPR171 and that ligands targeting GPR171 may eventually lead to therapeutics for food-related disorders.

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