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

Sci Signal. 2016 May 31;9(430):ra55. doi: 10.1126/scisignal.aac8035.


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.

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Appetite
  • Body Weight
  • CHO Cells
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • Eating / drug effects*
  • Feeding Behavior
  • Gene Expression Regulation
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / pharmacology
  • Neuropeptides
  • Peptides / pharmacology
  • Phthalic Acids / pharmacology*
  • Protein Binding
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction


  • Anilides
  • GPR171 protein, mouse
  • Ligands
  • MS0015203
  • Nerve Tissue Proteins
  • Neuropeptides
  • Pcsk1n protein, mouse
  • Peptides
  • Phthalic Acids
  • Receptors, G-Protein-Coupled
  • Calcium