G-protein coupled receptor 139 (GPC139) is aprotein that in humans is encoded by theGPR139gene.[5][6] Research has shown that mice with loss of GCP139 experience schizophrenia-like symptomatology that is rescued with the dopamine receptor antagonisthaloperidol and the μ-opioid receptor antagonistnaltrexone.[7][8]
GPR139 is activated by L-tryptophan and L-phenylalanine, though only at relatively high concentrations,[9] but in 2025, GPR139 was identified as a novelopioid receptor, specifically ofdynorphins.[10]
Zelatriazin (TAK-41), (NBI-1065846) a potent, and GPR139 receptor selective agonist[11] which was in clinical trials to gauge the efficacy for treating psychiatric conditions such asmajor depressive disorder and the negative symptoms ofschizophrenia, but was later dropped from development.
^Liu C, Bonaventure P, Lee G, Nepomuceno D, Kuei C, Wu J, et al. (Nov 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 (5):911–25.doi:10.1124/mol.115.100412.PMID26349500.
^Reichard HA, Schiffer HH, Monenschein H, Atienza JM, Corbett G, Skaggs AW, et al. (August 2021). "Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia".Journal of Medicinal Chemistry.64 (15):11527–11542.doi:10.1021/acs.jmedchem.1c00820.PMID34260228.S2CID235908256.
Vanti WB, Nguyen T, Cheng R, Lynch KR, George SR, O'Dowd BF (May 2003). "Novel human G-protein-coupled receptors".Biochemical and Biophysical Research Communications.305 (1):67–71.doi:10.1016/S0006-291X(03)00709-5.PMID12732197.
Ottolenghi C, Fellous M, Barbieri M, McElreavey K (March 2002). "Novel paralogy relations among human chromosomes support a link between the phylogeny of doublesex-related genes and the evolution of sex determination".Genomics.79 (3):333–343.doi:10.1006/geno.2002.6711.PMID11863363.
Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S (June 2002). "Identification of G protein-coupled receptor genes from the human genome sequence".FEBS Letters.520 (1–3):97–101.doi:10.1016/S0014-5793(02)02775-8.PMID12044878.S2CID7116392.
Gloriam DE, Schiöth HB, Fredriksson R (April 2005). "Nine new human Rhodopsin family G-protein coupled receptors: identification, sequence characterisation and evolutionary relationship".Biochimica et Biophysica Acta (BBA) - General Subjects.1722 (3):235–246.doi:10.1016/j.bbagen.2004.12.001.PMID15777626.
Matsuo A, Matsumoto S, Nagano M, Masumoto KH, Takasaki J, Matsumoto M, et al. (May 2005). "Molecular cloning and characterization of a novel Gq-coupled orphan receptor GPRg1 exclusively expressed in the central nervous system".Biochemical and Biophysical Research Communications.331 (1):363–369.doi:10.1016/j.bbrc.2005.03.174.PMID15845401.
