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The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site

2017; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/s41598-017-01049-z

2045-2322

Anne Cathrine Nøhr, Willem Jespers, Mohamed A. Shehata, Leonard Floryan, Vignir Ísberg, Kirsten B. Andersen, Johan Åqvist, Hugo Gutiérrez‐de‐Terán, Hans Bräuner‐Osborne, David E. Gloriam,

Chemical Synthesis and Analysis

GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson's disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi et al. and Dvorak et al. included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg et al. and Liu et al. have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca