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

Shehata, Mohamed A.; Nøhr, Anne Cathrine; Lissa, Delphine; Bisig, Christoph; Ísberg, Vignir; Andersen, Knud Erik; Harpsøe, Kasper; Björkling, Fredrik; Bräuner‐Osborne, Hans; Gloriam, David E.

doi:10.1038/srep36681

Cited by 22 publications

(37 citation statements)

References 22 publications

(46 reference statements)

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“…1). GPR139 has been shown to signal trough Gα s (Hu et al., 2009), Gα i (Süsens et al., 2006) and Gα q (Dvorak et al., 2015, Isberg et al., 2014, Liu et al., 2015, Matsuo et al., 2005, Shehata et al., 2016, Shi et al., 2011, Wang et al., 2015), however in CHO-k1 cells GPR139 only signals via the Gα q -coupled signaling pathway (Isberg et al., 2014, Shehata et al., 2016). The main signaling pathway of MC4R is through Gα s (reviewed in (Tao, 2010)).…”

Section: Discussionmentioning

confidence: 99%

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Nøhr

Shehata

Hauser

et al. 2017

Neurochemistry International

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GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle “similar targets bind similar ligands”, we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and β-melanocyte stimulating hormone (α-MSH and β-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, β-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.

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Section: Discussionmentioning

confidence: 99%

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Nøhr

Shehata

Hauser

et al. 2017

Neurochemistry International

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“…The approach has found new dipeptide ligands for the oGPCR GPR139 (ref. 65), suggesting an endogenous ligand chemotype.…”

Section: New Chemistry For New Targetsmentioning

confidence: 99%

Discovery of new GPCR ligands to illuminate new biology

2017

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Although a plurality of drugs target G-protein-coupled receptors (GPCRs), most have emerged from classical medicinal chemistry and pharmacology programs and resemble one another structurally and functionally. Though effective, these drugs are often promiscuous. With the realization that GPCRs signal via multiple pathways, and with the emergence of crystal structures for this family of proteins, there is an opportunity to target GPCRs with new chemotypes and confer new signaling modalities. We consider structure-based and physical screening methods that have led to the discovery of new reagents, focusing particularly on the former. We illustrate their use against previously untargeted or orphan GPCRs, against allosteric sites, and against classical orthosteric sites that selectively activate one downstream pathway over others. The ligands that emerge are often chemically novel, which can lead to new biological effects.

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“…Structures of selected GPR139 agonists (A) L‐tryptophan, (B) L‐phenylalanine, (C) α‐MSH, (D) tryptamine, (E) β‐phenylethylamine, (F) amphetamine, (G) LP‐360924 by Lexicon Pharmaceuticals, (H) cmp1a by H. Lundbeck A/S, (I) JNJ‐63533054 (also known as 7c) by Janssen Research and Development, (J) 39 by Takeda Pharmaceutical Company Limited, (K) DL43 a bioisostere of cmp1a and (L) AC4 …”

Section: Putative Endogenous Gpr139 Receptor Agonistsmentioning

confidence: 99%

Pharmacology and function of the orphan GPR139 G protein‐coupled receptor

Vedel

Nøhr

Gloriam

et al. 2019

Basic Clin Pharma Tox

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RECEPTORSG protein-coupled receptors (GPCRs) mediate many of the physiological responses to endogenous ligands such as neurotransmitters, hormones, metabolites, ions and sensory signals. 1 Although their ligands are structurally very diverse, GPCRs share a common molecular structure of seven transmembrane-spanning α-helices connected by three intracellular and three extracellular loops, with an extracellular N terminus and intracellular C terminus. 2 Amongst all of the drugs approved by the Food and Drug Administration (FDA), 34% target GPCRs 3 making this the largest class of drug targets. However, despite this, only 27% of all non-olfactory GPCRs are presently drug targets. Based on previous success with targeting this protein family and strongThis is an open access article under the terms of the Creat ive Commo ns Attri butio n NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractG protein-coupled receptors (GPCRs) constitute the largest family of receptors and membrane proteins in the human genome with ~800 members of which half are olfactory.GPCRs are activated by a very broad range of endogenous signalling molecules and are involved in a plethora of physiological functions. All GPCRs contain a transmembrane domain, consisting of a bundle of seven α-helices spanning the cell membrane, and forming the majority of the known ortho-or allosteric ligand binding sites. Due to their many physiological functions and the accessible and druggable transmembrane pocket, GPCRs constitute the largest family of drug targets mediating the actions of 34% of currently

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

Cited by 22 publications

References 22 publications

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW

Discovery of new GPCR ligands to illuminate new biology

Pharmacology and function of the orphan GPR139 G protein‐coupled receptor

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