Computer-Aided Discovery of Aromatic l-α-Amino Acids as Agonists of the Orphan G Protein-Coupled Receptor GPR139

Abstract

GPR139 is an orphan G protein-coupled receptor expressed mainly in the central nervous system. We developed a pharmacophore model based on known GPR139 surrogate agonists which led us to propose aromatic-containing dipeptides as potential ligands. Upon testing, the dipeptides demonstrated agonism in the Gq pathway. Next, in testing all 20 proteinogenic l-α-amino acids, L-tryptophan and l-phenylalanine were found to have EC50 values of 220 and 320 μM, respectively, making them the first putative endogenous agonists for GPR139.

Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139

“…It has been shown to have a high mRNA expression in the brain, particularly in the striatum and hypothalamus678 – suggesting that GPR139 could be involved in movement control789 and/or the regulation of food intake/metabolism610. GPR139 is thus a potential target for the treatment of Parkinson’s disease, obesity, eating disorders, and/or diabetes.…”

High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139

“…Additionally, this reaction could be inhibited by a G q/11 selective inhibitor [2] . This observation was confirmed through the discovery of a series of GPR139 agonists using calcium mobilization assays [7,8] . Susens et al identified the signal transduction pathway using both Ca 2+ mobilization and luciferase-reporter-gene assays.…”

“…However, Hu et al identified GPR139 as a Gs-coupled receptor because overexpressed GPR139 in HEK239 cells could increase basal intracellular cAMP concentrations [6] . Previous studies have shown that Gq-coupling is the main signaling pathway of GPR139 and might activate other pathways [8] . Furthermore, it was noted that GPR139 appears to be a monomer in HEK-293 cells and a dimer in CHO-K1 cells [3] .…”

“…Shi et al identified compound 1 as a GPR139 receptor agonist with an EC 50 of 39 nmol/L in a calcium mobilization assay for a CHO-K1 cell line stably expressing the human GPR139 for high-throughput screening (HTS) [7] . Isberg et al discovered dipeptides and L-α-amino acids as GPR139 agonists by building a pharmacophore model based on the characterization of 13 compounds reported by Shi et al [8] . Four dipeptides [TyrTrp (2), TyrPhe, TrpTyr, and TyrHis] consisting of aromatic amino acids were obtained.…”

Radiosynthesis and characterisation of a potent and selective GPR139 agonist radioligand

“…Next, we investigated the binding of To avoid the high level of binding to the lters and potential low specic binding due to a fast off-rate of the radioligand; SPA-bead binding, centrifugation-binding and whole cell binding was attempted, but none of these methods gave any GPR139 is expressed at the protein level in the CHO-k1 GPR139 cell line, as we have previously demonstrated a functional agonist response to 1 in the same cell line, 9 which was conrmed in the present study. Using qPCR analysis we furthermore veried the presence of GPR139 transcripts in the CHO-k1 GPR139 cell line but not in the CHO-k1 background cell line (Fig.…”