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EPPTB
EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.
EPPTB acts as a potent and selective trace amine-associated receptor 1 (TAAR1) full antagonist. Although EPPTB has high affinity for the mouse TAAR1 (mTAAR1) (Ki = 0.9 nM), it has much lower affinity for rat TAAR1 (rTAAR1) (Ki = 942 nM) and human TAAR1 (hTAAR1) (Ki = >5,000 nM), which limits its use in research. While the mTAAR1 and hTAAR1 have similar functions and bind similar ligands, the actual binding affinities of individual ligands often vary significantly between the two versions of the receptor.
Compared to the mTAAR1 (IC50 = 27.5 nM), EPPTB is 272-fold less potent at the hTAAR1 (IC50 = 7,487 nM) and 165-fold less potent at the rTAAR1 (IC50 = 4,539 nM) in vitro. EPPTB seems to not be an antagonist of the TAAR1 but rather an inverse agonist, reducing mTAAR1-stimulated cAMP production (–12.3 ± 4.7%).
EPPTB has no known significant activity at other targets besides the TAAR1.
EPPTB dramatically increases the firing rates of dopamine neurons in ventral tegmental area (VTA) slices and of serotonin neurons in dorsal raphe nucleus (DRN) slices ex vivo. Similarly, EPPTB enhances electrically evoked dopamine release in nucleus accumbens (NAcc) but not dorsal striatum (DStr) slices ex vivo. However, despite the increased dopamine neuron firing rates, basal extracellular dopamine levels in the striatum were not enhanced in TAAR1 knockout mice. EPPTB also blocks the suppression of dopamine neuron firing and evoked dopamine release in VTA and NAcc slices by TAAR1 agonists like tyramine and RO5166017 ex vivo. EPPTB blocked the suppression of DRN serotonin neuron firing by tyramine and RO5166017 as well. The preceding effects of EPPTB were absent in slices from TAAR1 knockout mice. As with ex vivo studies, EPPTB enhances VTA dopamine neuron firing rates in vivo in rats and prevents the suppression of the firing of these neurons by high doses of LSD (a serotonergic psychedelic and potent rodent TAAR1 agonist) and by apomorphine (a dopamine D2 receptor agonist). The inhibition of dopamine and serotonin neuron firing rates by TAAR1 signaling appears to be mediated by tonic activation of inwardly rectifying potassiums (IRK) channels and consequent neuronal inhibition.
The TAAR1 partial agonists RO5203648 and RO5263397 enhance the firing rates of dopamine and serotonin neurons in brain slices ex vivo. These findings suggest that the TAAR1 is constitutively and/or tonically active and that TAAR1 partial agonists produce net antagonism. However, TAAR1 partial agonists like RO5203648 have shown effects similar to those of TAAR1 full agonists like RO5166017 in vivo, for instance suppression of hyperlocomotion induced by psychostimulants like cocaine and dextroamphetamine and by NMDA receptor antagonists like L-687,414.
In an unpublished study, EPPTB was reported to substantially reduce methamphetamine-induced hyperlocomotion in mice chronically exposed to methamphetamine in vivo, an effect that was absent in TAAR1 knockout mice. This was interpreted as possible support for TAAR1 agonism mediating psychostimulant-like effects of amphetamines. In other research however, the low-efficacy and antagonist-like TAAR1 partial agonist RO5073012 (Emax ≈ 25% for mTAAR1) did not affect amphetamine-induced hyperlocomotion in normal mice and substantially rescued amphetamine-induced hyperlocomotion in the context of transgenic TAAR1 overexpression, a situation in which amphetamine-induced hyperlocomotion is otherwise weak and dramatically reduced compared to usual.
The TAAR1 agonist 3-iodothyronamine (T1AM), but not the TAAR1 agonists β-phenethylamine or tyramine, increased tyrosine hydroxylase (TA) phosphorylation and expected functional activity in DStr slices ex vivo. This effect involved CaMKII and PKA activation. In accordance with the enhanced expected TH activity, higher L-DOPA accumulation was observed in animals treated with T1AM and a DOPA decarboxylase inhibitor. These effects of T1AM were abolished by TAAR1 knockout and by EPPTB. In accordance with the preceding findings, T1AM also enhanced electrically evoked dopamine release in DStr slices ex vivo. This effect was likewise reduced by TAAR1 knockout and by EPPTB. By itself, EPPTB had no effect on evoked dopamine release in DStr slices ex vivo. The preceding findings conflict with previous results that TAAR1 signaling inhibits the firing rates of VTA dopamine neurons. These differing findings may be related to differential regulation of dopaminergic signaling in the VTA versus the DStr as well as other factors. On the other hand, previous studies have found that TAAR1 agonism blunted MDMA- and para-chloroamphetamine (PCA)-induced dopamine release in both the ventral and dorsal striatum.
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EPPTB
EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.
EPPTB acts as a potent and selective trace amine-associated receptor 1 (TAAR1) full antagonist. Although EPPTB has high affinity for the mouse TAAR1 (mTAAR1) (Ki = 0.9 nM), it has much lower affinity for rat TAAR1 (rTAAR1) (Ki = 942 nM) and human TAAR1 (hTAAR1) (Ki = >5,000 nM), which limits its use in research. While the mTAAR1 and hTAAR1 have similar functions and bind similar ligands, the actual binding affinities of individual ligands often vary significantly between the two versions of the receptor.
Compared to the mTAAR1 (IC50 = 27.5 nM), EPPTB is 272-fold less potent at the hTAAR1 (IC50 = 7,487 nM) and 165-fold less potent at the rTAAR1 (IC50 = 4,539 nM) in vitro. EPPTB seems to not be an antagonist of the TAAR1 but rather an inverse agonist, reducing mTAAR1-stimulated cAMP production (–12.3 ± 4.7%).
EPPTB has no known significant activity at other targets besides the TAAR1.
EPPTB dramatically increases the firing rates of dopamine neurons in ventral tegmental area (VTA) slices and of serotonin neurons in dorsal raphe nucleus (DRN) slices ex vivo. Similarly, EPPTB enhances electrically evoked dopamine release in nucleus accumbens (NAcc) but not dorsal striatum (DStr) slices ex vivo. However, despite the increased dopamine neuron firing rates, basal extracellular dopamine levels in the striatum were not enhanced in TAAR1 knockout mice. EPPTB also blocks the suppression of dopamine neuron firing and evoked dopamine release in VTA and NAcc slices by TAAR1 agonists like tyramine and RO5166017 ex vivo. EPPTB blocked the suppression of DRN serotonin neuron firing by tyramine and RO5166017 as well. The preceding effects of EPPTB were absent in slices from TAAR1 knockout mice. As with ex vivo studies, EPPTB enhances VTA dopamine neuron firing rates in vivo in rats and prevents the suppression of the firing of these neurons by high doses of LSD (a serotonergic psychedelic and potent rodent TAAR1 agonist) and by apomorphine (a dopamine D2 receptor agonist). The inhibition of dopamine and serotonin neuron firing rates by TAAR1 signaling appears to be mediated by tonic activation of inwardly rectifying potassiums (IRK) channels and consequent neuronal inhibition.
The TAAR1 partial agonists RO5203648 and RO5263397 enhance the firing rates of dopamine and serotonin neurons in brain slices ex vivo. These findings suggest that the TAAR1 is constitutively and/or tonically active and that TAAR1 partial agonists produce net antagonism. However, TAAR1 partial agonists like RO5203648 have shown effects similar to those of TAAR1 full agonists like RO5166017 in vivo, for instance suppression of hyperlocomotion induced by psychostimulants like cocaine and dextroamphetamine and by NMDA receptor antagonists like L-687,414.
In an unpublished study, EPPTB was reported to substantially reduce methamphetamine-induced hyperlocomotion in mice chronically exposed to methamphetamine in vivo, an effect that was absent in TAAR1 knockout mice. This was interpreted as possible support for TAAR1 agonism mediating psychostimulant-like effects of amphetamines. In other research however, the low-efficacy and antagonist-like TAAR1 partial agonist RO5073012 (Emax ≈ 25% for mTAAR1) did not affect amphetamine-induced hyperlocomotion in normal mice and substantially rescued amphetamine-induced hyperlocomotion in the context of transgenic TAAR1 overexpression, a situation in which amphetamine-induced hyperlocomotion is otherwise weak and dramatically reduced compared to usual.
The TAAR1 agonist 3-iodothyronamine (T1AM), but not the TAAR1 agonists β-phenethylamine or tyramine, increased tyrosine hydroxylase (TA) phosphorylation and expected functional activity in DStr slices ex vivo. This effect involved CaMKII and PKA activation. In accordance with the enhanced expected TH activity, higher L-DOPA accumulation was observed in animals treated with T1AM and a DOPA decarboxylase inhibitor. These effects of T1AM were abolished by TAAR1 knockout and by EPPTB. In accordance with the preceding findings, T1AM also enhanced electrically evoked dopamine release in DStr slices ex vivo. This effect was likewise reduced by TAAR1 knockout and by EPPTB. By itself, EPPTB had no effect on evoked dopamine release in DStr slices ex vivo. The preceding findings conflict with previous results that TAAR1 signaling inhibits the firing rates of VTA dopamine neurons. These differing findings may be related to differential regulation of dopaminergic signaling in the VTA versus the DStr as well as other factors. On the other hand, previous studies have found that TAAR1 agonism blunted MDMA- and para-chloroamphetamine (PCA)-induced dopamine release in both the ventral and dorsal striatum.