Discovery and SAR of a Series of Agonists at Orphan G Protein-Coupled Receptor 139

Abstract

GPR139 is an orphan G-protein coupled receptor (GPCR) which is primarily expressed in the central nervous system (CNS). In order to explore the biological function of this receptor, selective tool compounds are required. A screening campaign identified compound 1a as a high potency GPR139 agonist with an EC50 = 39 nM in a calcium mobilization assay in CHO-K1 cells stably expressing the GPR139 receptor. In the absence of a known endogenous ligand, the maximum effect was set as 100% for 1a. Screening against 90 diverse targets revealed no cross-reactivity issues. Assessment of the pharmacokinetic properties showed limited utility as in vivo tool compound in rat with a poor whole brain exposure of 61 ng/g and a brain/plasma (b/p) ratio of 0.03. Attempts to identify a more suitable analogue identified the des-nitrogen analogue 1s with a reduced polar surface area of 76.7 Å(2) and an improved b/p ratio of 2.8. The whole brain exposure remained low at 95 ng/g due to a low plasma exposure.

GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids l-Tryptophan and l-Phenylalanine

“…Information on the selectivity and pharmacokinetics of the GPR139 surrogate agonists previously published (TCO-9311 and LP-360924) are limited compared with those of JNJ-63533054. TCO 9311 was found to be a P-glycoprotein substrate with very limited ability to cross the blood-brain barrier (Shi et al, 2011). In contrast, JNJ-63533054 crosses the rat blood-brain barrier after oral administration and achieves exposure in the micromolar range (Dvorak et al, 2015).…”

“…In contrast, JNJ-63533054 crosses the rat blood-brain barrier after oral administration and achieves exposure in the micromolar range (Dvorak et al, 2015). Structurally, JNJ-63533054 possesses functional group elements that can be found in the reported hydrazinecarboxamide agonist (TCO-9311) (Shi et al, 2011) having two carbonyls in a 1,4 relationship, separated by two atoms and accompanied by a large flanking hydrophobic surface. It contains fewer hydrogen bond donors and acceptors than does the hydrazinecarboxamide agonist and thus was found to have better physicochemical properties.…”

“…To date, three groups have reported surrogate small molecules for GPR139. Shi et al (2011) identified a series of benzohydrazides as potent and selective surrogate agonists for GPR139; the most potent compound is also known as TCO-9311 (3,5-dimethoxybenzoic acid 2-[(1-naphthalenylamino)carbonyl] hydrazide). Hu et al (2009) also identified surrogate agonists amino)-1,3,5-triazin-2-yl)amino)-4-phenylthiazol-5-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone) and antagonists (LP-471756 4-cyclohexyl-N-(o-tolyl)benzenesulfonamide and LP-114958 3-benzyl-N,5-dicyclohexyl-3H- [1,2,3]triazolo [4,5-day]pyrimihdin-7-amine) for GPR139.…”

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.…”

“…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] .…”