Summary of the probe development effort to identify antagonists of the human trace amine associated receptor 1 (TAAR1)
Name: Summary of the probe development effort to identify antagonists of the human trace amine associated receptor 1 (TAAR1). ..more
Depositor Specified Assays
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: RTI International
Assay Provider: Brian P. Gilmour, RTI International
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1R21NS064780-01A1
Grant Proposal PI: Brian P. Gilmour, RTI International
External Assay ID: TAAR1_ANT_SUMMARY
Name: Summary of the probe development effort to identify antagonists of the human trace amine associated receptor 1 (TAAR1).
Heterotrimeric G-protein coupled receptors (GPCRs) are major targets for disease therapeutics, due in part to their broad tissue distribution, structural diversity, varied modes of action, and disease-associated mutations (1-4). TAAR1 (trace amine associated receptor 1) is a G protein-coupled receptor activated by trace amines. Trace amines (TA) such as Beta-phenethylamine (Beta-PEA), p-tyramine (TYR), octopamine, and tryptamine are endogenous amine compounds that account for less than 1% of the biogenic amines in most brain regions (5), and exert pharmacological actions in humans (6,7). In addition to binding Beta-PEA and TYR, rat TAAR1 is also activated by dopamine, octopamine, tryptamine, amphetamine, and lysergic acid (8-10). TAs are of particular interest because they have been shown to modulate the activity of neurotransmitters such as dopamine (11-13) and gamma-amino butyric acid (14-16) and alterations in their brain levels are associated with schizophrenia (17-19) and depression (20, 21). Their potential to modulate dopaminergic activity suggests that they may play a role in the efficacy of L-DOPA in treating Parkinson disease4 and addiction (13). In humans, only TAAR1 has been shown to be activated by Beta-PEA and TYR, resulting in increased cyclic adenosine monophosphate (cAMP) accumulation through coupling to Gs (9, 10). Endogenous hTAAR1 activity is predominantly coupled to G-alpha-s and the accumulation of cAMP. The variety of compounds potentially acting at this receptor makes it attractive to assume that hTAAR1 is involved in a variety of integrated CNS processes such as mood and cognition. As a result, hTAAR1 is an interesting target for the development of ligands to probe the role of this receptor in CNS function and disease. For this project, the assay provider has created a cell line expressing the hTAAR1 in a parent cell line (RD-HGA16 cells, Molecular Devices) that stably over expresses the promiscuous G-protein, G-alpha-16, thereby coupling hTAAR1 activation to mobilization of internal calcium stores. Because TAs may be involved in modulating a variety of behaviors including mood, cognition, and addiction, it is of interest to discover novel ligands for TAAR1 to probe the role TAs play in brain function (22, 23).
Summary of Probe Development Effort:
This probe development effort is focused on the identification of antagonists of the human trace amine associated receptor 1 (TAAR1). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Pan, H.L., Wu, Z.Z., Zhou, H.Y., Chen, S.R., Zhang, H.M., and Li, D.P., Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther, 2008. 117(1): p. 141-61.
2. Lagerstrom, M.C. and Schioth, H.B., Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov, 2008. 7(4): p. 339-57.
3. Thompson, M.D., Cole, D.E., and Jose, P.A., Pharmacogenomics of G protein-coupled receptor signaling: insights from health and disease. Methods Mol Biol, 2008. 448: p. 77-107.
4. Bosier, B. and Hermans, E., Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol Sci, 2007. 28(8): p. 438-46.
5. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001 Dec;60(6):1181-8.
6. Premont RT, Gainetdinov RR, Caron MG: Following the trace of elusive amines. Proc Natl Acad Sci U S A 2001;98:9474-9475.
7. Branchek TA, Blackburn TP: Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr Opin Pharmacol 2003;3:90-97.
8. Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al: Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A 2001;98:8966-8971.
9. Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, et al: Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 2001;60:1181-1188.
10. Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC: Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 2005;85:372-385.
11. Jones RS: Specific enhancement of neuronal responses to catecholamine by p-tyramine. J Neurosci Res 1981;6:49-61.
12. Mercuri NB, Bernardi G: The "magic" of L-dopa: why is it the gold standard Parkinson's disease therapy? Trends Pharmacol Sci 2005;26:341-344.
13. Miller GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, et al: Primate trace amine receptor 1 modulation by the dopamine transporter. J Pharmacol Exp Ther 2005;313:983-994.
14. Dourish CT, Cooper SJ: Pharmacology of beta-phenylethylamine induced seizures in mice. Prog Neuropsychopharmacol Biol Psychiatry 1983;7:787-790.
15. Berretta N, Giustizieri M, Bernardi G, Mercuri NB: Trace amines reduce GABA(B) receptor-mediated presynaptic inhibition at GABAergic synapses of the rat substantia nigra pars compacta. Brain Res 2005;1062:175-178.
16. Federici M, Geracitano R, Tozzi A, Longone P, Di Angelantonio S, Bengtson CP, et al: Trace amines depress GABA B response in dopaminergic neurons by inhibiting G-betagamma-gated inwardly rectifying potassium channels. Mol Pharmacol 2005;67:1283-1290.
17. Boulton AA: Some aspects of basic psychopharmacology: the trace amines. Prog Neuropsychopharmacol Biol Psychiatry 1982;6:563-570.
18. Anderson GM, Gerner RH, Cohen DJ, Fairbanks L: Central tryptamine turnover in depression, schizophrenia, and anorexia: measurement of indoleacetic acid in cerebrospinal fluid. Biol Psychiatry 1984;19: 1427-1435.
19. Duan J, Martinez M, Sanders AR, Hou C, Saitou N, Kitano T, et al: Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet 2004;75:624-638.
20. Davis BA, Boulton AA: The trace amines and their acidic metabolites in depression-an overview. Prog Neuropsychopharmacol Biol Psychiatry 1994;18:17-45.
21. Baker GB, Coutts RT, Greenshaw AJ: Neurochemical and metabolic aspects of antidepressants: an overview. J Psychiatry Neurosci 2000; 25:481-496.
22. Navarro HA, Gilmour BP, Lewin AH. A rapid functional assay for the human trace amine-associated receptor 1 based on the mobilization of internal calcium. J Biomol Screen. 2006 Sep;11(6):688-93. Epub 2006 Jul 10.
23. Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B. The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20081-6.
Summary, Summary AID, primary screen, primary, mood, cognition, addiction, ANT, INH, FLIPR, TAAR1, hTAAR1, MGC126874, MGC138399, RP11-295F4.9, TA1, TAR1, TRAR1, receptor, taR-1, trace amine receptor, trace amine-associated receptor 1, GPCR, Fluo-8, FLUO8, RD-HGA, RD-HGA16, cells, cell-based, CHO, dye, calcium, kinetic, fluorescence, antagonist, antagonism, inhibitor, inhibit, decrease, primary screen, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.