Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139.
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.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
Vignir
V
Isberg
Kirsten B
KB
Andersen
Christoph
C
Bisig
Gunnar P H
GP
Dietz
Hans
H
Bräuner-Osborne
David E
DE
Gloriam
D024322:Amino Acids, Aromatic / Q000737:chemistry* / Q000494:pharmacology*; D017076:Computer-Aided Design; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry / Q000494:pharmacology
D024322:Amino Acids, Aromatic; D004151:Dipeptides; C501535:GPR139 protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D010649:Phenylalanine; D014364:Tryptophan