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

Abstract

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.

Quantitative Mass Spectrometry Reveals Food Intake-Induced Neuropeptide Level Changes in Rat Brain: Functional Assessment of Selected Neuropeptides as Feeding Regulators

“…Moreover, ProSAAS-derived peptides were also shown to colocalize with the feeding-regulatory peptide NPY in the mouse HT, and were concentrated in the arcuate nucleus (37). Because the receptors for several ProSAAS-derived peptides such as big LEN and PEN have been identified (50,51), a small-molecule ligand of GPR171, a hypothalamic G proteincoupled receptor for Big LEN, was screened and demonstrated to increase food intake in mice through the activation of GPR171 (52). Taken together, these studies suggested the potential function of ProSAAS peptides as regulators of food intake.…”

How Ligands Illuminate GPCR Molecular Pharmacology

“…One GPR68 PAM, ogerin, was demonstrated to have on-target activity in vivo by modulating conditioned fear responses in mice. A similar approach has recently been used to identify small molecule ligands for the oGPCRs GPR171 (Wardman et al, 2016) and MRGPRX2 (Lansu et al, 2017), and these compounds were subsequently used to further characterize the receptor’s role in feeding behavior and itch, respectively.…”

Discovery of new GPCR ligands to illuminate new biology

“…A docking screen of 10,526 in-house compounds against a homology model of GPR171 (ref. 61) identified a dicarboxyphenyl vinyl amide, MS0015203 (ZINC4956098; MW 249), as an orthosteric agonist 61 . MS0015203 had activity in vivo in modulating feeding, which is unusual for a primary fragment hit.…”