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| Other names | Ro 5212773; Ro-5212773; Ro5212773; RO-5212773; RO5212773 |
| Drug class | TAAR1 antagonist |
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| Formula | C20H21F3N2O2 |
| Molar mass | 378.395 g·mol−1 |
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EPPTB (developmental code name RO-5212773) is a drug developed by Hoffmann-La Roche which acts as a potent and selective inverse agonist of the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. EPPTB is one of the first selective antagonists developed for the TAAR1, and has been used to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.[1]
Although EPPTB has high affinity for the mouse TAAR1, it has much lower affinity for rat and human TAAR1, which limits its use in research.[2] While the human and mouse forms of TAAR1 have similar functions and bind similar ligands, the actual binding affinities of individual ligands often vary significantly between the two versions of the receptor.[3] Compared to the mouse TAAR1 (IC50 = 27.5 nM), EPPTB is 272-fold less potent at the human TAAR1 (IC50 = 7.5 μM) and 165-fold less potent at the rat TAAR1 (IC50 = 4.5 μM) in vitro.[4] EPPTB seems to not be an antagonist of the TAAR1 but rather an inverse agonist, reducing mTAAR1-stimulated cAMP production (–12.3 ± 4.7%).[4]
EPPTB crosses the blood–brain barrier and has a favorable ratio of brain-to-plasma concentrations.[4] Systemic administration produces centrally mediated effects in animals.[4] However, the drug has high clearance and this has limited its research usefulness.[4]
EPPTB is an antagonist of the effects of monoaminergic activity enhancers (MAEs) like benzofuranylpropylaminopentane (BPAP) and selegiline, for instance enhancement of dopamine release in the striatum.[5][6] In relation to this, the effects of these drugs appear to be mediated by TAAR1 agonism.[5][6]
See also
References
- ^ Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, et al. (November 2009). "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proceedings of the National Academy of Sciences of the United States of America. 106 (47): 20081–6. Bibcode:2009PNAS..10620081B. doi:10.1073/pnas.0906522106. PMC 2785295. PMID 19892733.
- ^ Stalder H, Hoener MC, Norcross RD (February 2011). "Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773)". Bioorganic & Medicinal Chemistry Letters. 21 (4): 1227–31. doi:10.1016/j.bmcl.2010.12.075. PMID 21237643.
- ^ Hu LA, Zhou T, Ahn J, Wang S, Zhou J, Hu Y, Liu Q (October 2009). "Human and mouse trace amine-associated receptor 1 have distinct pharmacology towards endogenous monoamines and imidazoline receptor ligands". The Biochemical Journal. 424 (1): 39–45. doi:10.1042/BJ20090998. PMID 19725810. S2CID 21498991.
- ^ a b c d e Decker AM, Brackeen MF, Mohammadkhani A, Kormos CM, Hesk D, Borgland SL, Blough BE (April 2022). "Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist". ACS Chem Neurosci. 13 (7): 1082–1095. doi:10.1021/acschemneuro.2c00086. PMC 9730857. PMID 35325532.
EPPTB is a potent mTAAR1 antagonist (IC50 = 27.5 nM) but is 272-fold and 165-fold less potent at hTAAR1 (IC50 = 7.5 μM) and rTAAR1 (IC50 = 4.5 μM), respectively.14 Additional studies have shown that EPPTB may be an inverse agonist, as the compound was able to reduce mTAAR1-stimulated cAMP production (−12.3 ± 4.7%).14 Because of its favorable brain/plasma ratio of 0.5, EPPTB has been used in animal studies examining DA neurotransmission,14 but its high clearance limits the extent of studies that can be performed.1,15–16 Therefore, additional antagonists with better ADME properties and potency profiles are needed to help further explore TAAR1 pharmacology.1,16
- ^ a b Harsing LG, Knoll J, Miklya I (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". Int J Mol Sci. 23 (15): 8543. doi:10.3390/ijms23158543. PMC 9369307. PMID 35955676.
- ^ a b Harsing LG, Timar J, Miklya I (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci. 24 (17): 13334. doi:10.3390/ijms241713334. PMC 10487936. PMID 37686140.
