Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): Discovery of EPPTB (RO5212773)

Stalder, Henri; Hoener, Marius C.; Norcross, Roger D.

doi:10.1016/j.bmcl.2010.12.075

Cited by 52 publications

(40 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has been confirmed after expression of TAAR1 in a variety of cell types and with various approaches to analyze cAMP concentrations used (Reese et al, 2007;Wainscott et al, 2007;Barak et al, 2008;Hu et al, 2009;Espinoza et al, 2011;Revel et al, 2011;Liu et al, 2014). In fact, cAMP assays are now a central component of TAAR1 ligand screening programs (Bradaia et al, 2009;Revel et al, 2011Revel et al, , 2012aRevel et al, , 2013Stalder et al, 2011;Galley et al, 2012Galley et al, , 2015.…”

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 82%

“…Clear differentiation between these two possible scenarios has not been possible. Further confusing the situation are suggestions that EPPTB may in fact be an inverse agonist (Bradaia et al, 2009;Stalder et al, 2011). EPPTB also blocks the TAAR1-mediated activation of an inwardly rectifying K + current in VTA slices (Bradaia et al, 2009).…”

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 99%

“…Thus far, only one such compound, EPPTB [N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl)benzamide (RO5212773)] (Fig. 2), has been identified and characterized (Bradaia et al, 2009;Stalder et al, 2011). EPPTB is a highly potent mouse TAAR1-selective antagonist that is largely inactive at the rat and human isoforms (Berry et al, 2017); unfortunately, even in mice, the pharmacokinetic properties prevent the in vivo use of EPPTB (Bradaia et al, 2009).…”

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 99%

See 2 more Smart Citations

Trace Amines and Their Receptors

Gainetdinov¹,

Hoener²,

Berry³

2018

Pharmacol Rev

Self Cite

258

251

View full text Add to dashboard Cite

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 82%

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 99%

Section: Ro5166017 [(S)-4-((ethyl(phenyl)-amino)methyl)-45-dihydrooxmentioning

confidence: 99%

See 1 more Smart Citation

Trace Amines and Their Receptors

Gainetdinov¹,

Hoener²,

Berry³

2018

Pharmacol Rev

Self Cite

258

251

View full text Add to dashboard Cite

“…Such polypharmacology has made it challenging to understand the role and the biology of TAAR1. The recent discovery of a potent and selective TAAR1 antagonist (EPPTB, RO5212773) (Bradaia et al, 2009;Stalder et al, 2011) and an agonist (RO5166017) (Revel et al, 2011) is expected to facilitate the understanding of TAAR1 physiological functions and therapeutic potential. In vitro, use of these agents revealed that TAAR1 interacts functionally with the D 2 and 5-HT 1A receptors and modifies their pharmacological properties (Bradaia et al, 2009;Revel et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Brain-Specific Overexpression of Trace Amine-Associated Receptor 1 Alters Monoaminergic Neurotransmission and Decreases Sensitivity to Amphetamine

Revel

Meyer

Bradaı̈a³

et al. 2012

Neuropsychopharmacol

100

View full text Add to dashboard Cite

Trace amines (TAs) such as β-phenylethylamine, p-tyramine, or tryptamine are biogenic amines found in the brain at low concentrations that have been implicated in various neuropsychiatric disorders like schizophrenia, depression, or attention deficit hyperactivity disorder. TAs are ligands for the recently identified trace amine-associated receptor 1 (TAAR1), an important modulator of monoamine neurotransmission. Here, we sought to investigate the consequences of TAAR1 hypersignaling by generating a transgenic mouse line overexpressing Taar1 specifically in neurons. Taar1 transgenic mice did not show overt behavioral abnormalities under baseline conditions, despite augmented extracellular levels of dopamine and noradrenaline in the accumbens nucleus (Acb) and of serotonin in the medial prefrontal cortex. In vitro, this was correlated with an elevated spontaneous firing rate of monoaminergic neurons in the ventral tegmental area, dorsal raphe nucleus, and locus coeruleus as the result of ectopic TAAR1 expression. Furthermore, Taar1 transgenic mice were hyposensitive to the psychostimulant effects of amphetamine, as it produced only a weak locomotor activation and failed to alter catecholamine release in the Acb. Attenuating TAAR1 activity with the selective partial agonist RO5073012 restored the stimulating effects of amphetamine on locomotion. Overall, these data show that Taar1 brain overexpression causes hyposensitivity to amphetamine and alterations of monoaminergic neurotransmission. These observations confirm the modulatory role of TAAR1 on monoamine activity and suggest that in vivo the receptor is either constitutively active and/or tonically activated by ambient levels of endogenous agonist(s).

show abstract

“…Though EPPTB (N-(3-ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide) was described as a selective TA 1 R antagonist (Bradaia et al, 2009;Stalder et al, 2011), it is not centrally active upon systemic administration. The present study addressed the role of TA 1 R in the physiological, neurochemical, and behavioral actions of MDMA by exploiting TA 1 -KO mice.…”

Section: Introductionmentioning

confidence: 99%