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, testing all 20 proteinogenic L-α-amino acids; L-tryptophan and L-phenylalanine were found to have EC50 values of 220 µM and 320 µM, respectively, making them the first putative endogenous agonists for GPR139.