Hot topics: The orphan GPR139 receptor is activated by peptides

GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression in the striatum and hypothalamus, regions regulating locomotion and metabolism, respectively, and it has therefore been suggested as a potential target for Parkinson’s disease and metabolic syndrome. Surrogate ligands have been published by Lundbeck A/S [1], Jansen R&D [2], Takeda Pharmaceuticals [3], as well as the University of Copenhagen (Gloriam group). In a new publication, the latter group describe the first combined structure-activity relationships of all surrogate agonist, and a common pharmacophore model for future ligand identification and optimization [4].

The physiological agonist of GPR139 is still elusive. GPR139 has previously been shown to be activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 μM and 320 μM, respectively) [5,6], as well as di-peptides [5]. A new publication shows that the endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone and α- and β-melanocyte stimulating hormone in the low micromolar range. In addition, a potentially novel subpeptide (from consensus cleavage site) represents the most potent putative endogenous activator, so far (EC50 value of 600 nM) [7]. Together, these results indicate that GPR139 is a likely to be a peptide receptor that could act as a secondary target for melanocortin peptides or a yet undiscovered physiological ligand.

[1] Shi, F. (2011). Discovery and SAR of a series of agonists at orphan G protein-coupled receptor 139. ACS Med. Chem. Lett. 2, 303–306. doi:10.1021/ml100293q. PMID: 24900311

[2] Dvorak, C. (2015). Identification and SAR of glycine benzamides as potent agonists for the GPR139 Receptor. ACS Med. Chem. Lett. 6, 1015–1018. 10.1021/acsmedchemlett.5b00247. PMID: 26396690

[3] Hitchchock, S. (2016). 4-oxo-3,4-dihyroI-1,2,3-benzotriazine modulators of GPR139. US Patent US2016/0145218 A1. Takeda Pharmaceutical Company Limited

[4] Shehata, M.A. (2016). Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep. 6, 36681. doi:10.1038/srep36681. PMID: 27830715

[5] Isberg, V. et al. (2014). Computer-aided discovery of aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J. Chem. Inf. Model. 54, 1553–1557. doi: 10.1021/ci500197a. PMID: 24826842

[6] Liu, C. (2015). GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine. Mol. Pharmacol. 88, 911–925. doi: 10.1124/mol.115.100412. PMID: 26349500

[7] Nøhr, A.C. et al. (2016). 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. Neurochem. Int. 102, 105–113. doi: 10.1016/j.neuint.2016.11.012. PMID: 27916541

Comments by David E. Gloriam and Anne Cathrine Nøhr Jensen (Department of Drug Design and Pharmacology, University of Copenhagen)