EPPTB

Last updated
EPPTB
EPPTB2DCSD.svg
Clinical data
Other namesRo 5212773; Ro-5212773; Ro5212773; RO-5212773; RO5212773
Drug class Trace amine-associated receptor 1 (TAAR1) antagonist
Identifiers
  • N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H21F3N2O2
Molar mass 378.395 g·mol−1
3D model (JSmol)
  • CCOc2cc(ccc2)NC(=O)c(cc1C(F)(F)F)ccc1N3CCCC3

  • CCOc1cccc(c1)NC(=O)c2ccc(c(c2)C(F)(F)F)N3CCCC3
  • InChI=1S/C20H21F3N2O2/c1-2-27-16-7-5-6-15(13-16)24-19(26)14-8-9-18(25-10-3-4-11-25)17(12-14)20(21,22)23/h5-9,12-13H,2-4,10-11H2,1H3,(H,24,26)
  • Key:KLFVWQCQUXXLOU-UHFFFAOYSA-N

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). [1] [2] [3] The drug was the first selective antagonist developed for the TAAR1. [2] [3] It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. [4] [2] [3] EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system. [2] [3]

Contents

Pharmacology

Pharmacodynamics

Actions

EPPTB acts as a potent and selective trace amine-associated receptor 1 (TAAR1) full antagonist. [2] [3] 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. [3] 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. [5]

Compared to the mTAAR1 (IC50 Tooltip half-maximal inhibitory concentration = 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 . [4] [2] EPPTB seems to not be an antagonist of the TAAR1 but rather an inverse agonist, reducing mTAAR1-stimulated cAMP production (–12.3 ± 4.7%). [3] [4]

EPPTB at TAAR1 in different species [3] [2] [4]
Species Affinity (Ki, nM) IC50 Tooltip half-maximal inhibitory concentration (nM) Emax Tooltip maximal efficacy (%)
Mouse 0.927.5–12%
Rat 9424,539ND
Human >5,0007,487ND

EPPTB has no known significant activity at other targets besides the TAAR1. [2] [3]

Effects

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 . [1] [6] [2] [7] [8] Similarly, EPPTB enhances electrically evoked dopamine release in nucleus accumbens (NAcc) but not dorsal striatum (DStr) slices ex vivo. [7] However, despite the increased dopamine neuron firing rates, basal extracellular dopamine levels in the striatum were not enhanced in TAAR1 knockout mice. [9] [10] 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. [11] [2] [7] [8] EPPTB blocked the suppression of DRN serotonin neuron firing by tyramine and RO5166017 as well. [12] [8] The preceding effects of EPPTB were absent in slices from TAAR1 knockout mice. [1] [2] [7] 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). [13] [1] [14] 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. [11] [15] [2] [8]

The TAAR1 partial agonists RO5203648 and RO5263397 enhance the firing rates of dopamine and serotonin neurons in brain slices ex vivo. [6] [12] These findings suggest that the TAAR1 is constitutively and/or tonically active and that TAAR1 partial agonists produce net antagonism. [6] [12] 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. [11] [6]

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. [16] [17] [9] This effect involved CaMKII and PKA activation. [16] [9] In accordance with the enhanced expected TH activity, higher L-DOPA accumulation was observed in animals treated with T1AM and a DOPA decarboxylase inhibitor. [17] [9] These effects of T1AM were abolished by TAAR1 knockout and by EPPTB. [9] In accordance with the preceding findings, T1AM also enhanced electrically evoked dopamine release in DStr slices ex vivo. [9] This effect was likewise reduced by TAAR1 knockout and by EPPTB. [9] By itself, EPPTB had no effect on evoked dopamine release in DStr slices ex vivo. [9] The preceding findings conflict with previous results that TAAR1 signaling inhibits the firing rates of VTA dopamine neurons. [9] These differing findings may be related to differential regulation of dopaminergic signaling in the VTA versus the DStr as well as other factors. [9] 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. [9] [18]

Owing to their pro-dopaminergic effects, TAAR1 antagonists like EPPTB are not expected to be useful in the treatment of drug addiction, but might be useful in the treatment of hypodopaminergic conditions like Parkinson's disease. [11] Relatedly, systemic or intra-NAcc shell administration of the TAAR1 agonist reduced drug-induced reinstatement of cocaine-seeking in rats and prevented drug priming-induced CaMKIIα activation in the NAcc shell. [19] CaMKIIα was inhibited but PKA, PKC, ERK1/2, CREB, or GSK3β were unaffected in NAcc slices from rats administered RO5166017. [19] The behavioral effects were blocked by viral expression of CaMKIIα in the NAcc shell. [19] In contrast to RO5166017, injection of EPPTB into the NAcc shell augmented drug-induced reinstatement of cocaine-seeking and enhanced CAMKIIα activity. [19]

Neither EPPTB, RO5166017, nor TAAR1 KO affected dopamine reuptake in NAcc or DStr slices ex vivo, indicating that TAAR1 does not affect the function of the dopamine transporter (DAT). [7] These findings contradict previous findings of the TAAR1 modulating DAT activity that were mostly from in-vitro cell culture studies conducted by a single research group. [7] [20] On the other hand, EPPTB has been found to increase the affinity of dopamine for the dopamine D2 receptor and to reduce the desensitization rate of these receptors in VTA slices ex vivo, similarly to what has been observed for TAAR1 knockout mice. [15] [2] Likewise, EPPTB reduced the desensitization rate of serotonin 5-HT1A receptors in DRN slices ex vivo. [8]

EPPTB does not affect anxiety or has anxiolytic effects in the elevated plus maze and does not affect locomotor activity in the open field test in animals. [19] [21] Similarly, locomotion is unchanged in TAAR1 knockout mice. [10] In contrast to EPPTB, TAAR1 agonists show anxiolytic or anxiogenic effects in different studies as well as hypolocomotive effects. [19] [21] EPPTB has shown anticonvulsant [22] and neuroprotective effects in preclinical research. [23] EPPTB has been found to reduce the 5-hydroxytryptophan (5-HTP)-induced but not psilocybin-induced head-twitch response (HTR) in rodents. [24] [25]

EPPTB is an antagonist of the effects of monoaminergic activity enhancers (MAEs) like selegiline and benzofuranylpropylaminopentane (BPAP) in vitro, for instance enhancement of exocytotic dopamine release in the striatum. [26] [27] Selegiline is a weak mTAAR1 agonist in vitro. [28] In relation to the preceding, it has been hypothesized that the effects of MAEs may be mediated by TAAR1 agonism. [26] [27]

Pharmacokinetics

EPPTB shows good bioavailability with intraperitoneal administration. [3] It crosses the blood–brain barrier and has a favorable ratio of brain-to-plasma concentrations (0.5). [4] [3] Systemic administration produces centrally mediated effects in animals. [4] However, the drug has high clearance, and this has limited its research usefulness. [4] [3]

History

EPPTB was first described in the scientific literature by 2009. [2] [3] It was the first selective antagonist of the TAAR1 to be discovered. [2] [3] The drug was identified via high-throughput screening (HTS) of approximately 788,000 compounds followed by structure–activity optimization. [2] [3] For many years, EPPTB was the only TAAR1 antagonist available for scientific research. [1] [11] In 2022 however, the TAAR1 antagonist RTI-7470-44, a potent antagonist of the hTAAR1 and to a much lesser extent of the mTAAR1 and rTAAR1, was described. [29] [30] [31] [4]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">3-Iodothyronamine</span> Chemical compound

3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor. T1AM is the most potent endogenous TAAR1 agonist yet discovered. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output. Wu et al. have pointed out that this relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<i>N</i>-Methylphenethylamine Chemical compound

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">RO5166017</span> Chemical compound

RO5166017, or RO-5166017, is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. It is a partial agonist or near-full agonist depending on the species.

<i>o</i>-Phenyl-3-iodotyramine Chemical compound

o-Phenyl-3-iodotyramine (o-PIT) is a drug which acts as a selective agonist for the trace amine-associated receptor 1. It has reasonable selectivity for TAAR1 but relatively low potency, and is rapidly metabolised in vivo, making it less useful for research than newer ligands such as RO5166017.

The rostromedial tegmental nucleus (RMTg), also known as the tail of the ventral tegmental area (tVTA), is a GABAergic nucleus which functions as a "master brake" for the midbrain dopamine system. This region was discovered by the researchers, M. Barrot, J.Kaufling and T. Jhou. It is poorly differentiated from the rest of the ventral tegmental area (VTA) and possesses robust functional and structural links to the dopamine pathways. Notably, both acute and chronic exposure to psychostimulants have been shown to induce FosB and ΔFosB expression in the RMTg; no other drug type has been shown to induce these proteins in the RMTg.

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

<span class="mw-page-title-main">RTI-7470-44</span> Potent human TAAR1 antagonist

RTI-7470-44 is a potent and selective antagonist of the human trace amine-associated receptor 1 (TAAR1) which is used in scientific research. It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1 inverse agonist EPPTB in 2009.

<span class="mw-page-title-main">RO5263397</span> TAAR1 agonist

RO5263397, or RO-5263397, is a trace amine-associated receptor 1 (TAAR1) partial agonist which is used in scientific research.

<span class="mw-page-title-main">RO5203648</span> Pharmaceutical compound

RO5203648 is a trace amine-associated receptor 1 (TAAR1) partial agonist. It is a potent and highly selective partial agonist of both rodent and primate TAAR1. The drug suppresses the effects of psychostimulants like cocaine and methamphetamine. It also produces a variety of other behavioral effects, such as antidepressant-like, antipsychotic-like, and antiaddictive effects. Research with RO5203648 has led to interest in TAAR1 agonists for potential treatment of drug addiction. RO5203648 itself was not developed for potential medical use due to poor expected human pharmacokinetics.

References

  1. 1 2 3 4 5 Liu JF, Li JX (2018). "TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg". Front Pharmacol. 9: 279. doi: 10.3389/fphar.2018.00279 . PMC   5881156 . PMID   29636691. Hallucinogens: Lysergic acid diethylamide (LSD) has been reported as a TAAR1 agonist (Bunzow et al., 2001). Treatment with a TAAR1 antagonist EPPTB significantly blocked the inhibitory effect of LSD on dopaminergic neurons (De Gregorio et al., 2016). [...] Intriguingly, the TAAR1 agonist RO5166017 inhibited while the TAAR1 antagonist EPPTB promoted the firing rates of dopamine neurons in VTA and serotonin neurons in dorsal raphe nucleus (Revel et al., 2011). Moreover, dopamine neurons and serotonin neurons of TAAR1-KO mice showed increased firing rates (Revel et al., 2011).
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 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): 20081–20086. Bibcode:2009PNAS..10620081B. doi: 10.1073/pnas.0906522106 . PMC   2785295 . PMID   19892733.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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): 1227–1231. doi:10.1016/j.bmcl.2010.12.075. PMID   21237643.
  4. 1 2 3 4 5 6 7 8 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
  5. ↑ 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.
  6. 1 2 3 4 Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD, Bradaia A, Kilduff TS, Biemans B, Pouzet B, Caron MG, Canales JJ, Wallace TL, Wettstein JG, Hoener MC (December 2012). "Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics". Biol Psychiatry. 72 (11): 934–942. doi:10.1016/j.biopsych.2012.05.014. PMID   22705041. TAAR1 agonists, such as p-tyramine or the synthetic agonist RO5166017, inhibit the firing frequency of VTA DA neurons and DRN 5-HT neurons, whereas the TAAR1 antagonist EPPTB dramatically increases their firing rates (11,12). [...] Interestingly, RO5203648 blocked hyperdopaminergic- and hypoglutamatergic-induced hyperlocomotion in vivo, similar to the "full" agonist RO5166017 (11), whereas it increased firing activity of DA and 5-HT neurons in vitro, similar to the antagonist EPPTB (11,12). This observation indicates that, in vitro, TAAR1 is constitutively active and/or tonically activated by endogenous agonist(s), a situation where partial agonism produces antagonistic-like effects on firing activity. [...] The only selective TAAR1 antagonist currently available is EPPTB (RO5212773) (Bradaia et al., 2009). Pharmacological characterization suggests that EPPTB is a TAAR1 antagonist/inverse agonist (Stalder et al., 2011). EPPTB could increase the firing rate of DA neurons in the brain slice of VTA from WT mice but not from TAAR1-KO mice. EPPTB also prevented TAAR1 agonist p-tyramine (p-try)-induced reduction of the firing rate of DA neurons (Bradaia et al., 2009). The information on the in vivo pharmacological activities of EPPTB is sparse. Therefore, more systematic studies of EPPTB in vivo and the development of new TAAR1 antagonists would greatly boost the TAAR1 research.
  7. 1 2 3 4 5 6 Leo D, Mus L, Espinoza S, Hoener MC, Sotnikova TD, Gainetdinov RR (June 2014). "Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors". Neuropharmacology. 81: 283–291. doi:10.1016/j.neuropharm.2014.02.007. PMID   24565640. None of the drugs applied changed DA uptake because the Tau and half-life values were comparable among the naïve and treated brain slices (data not shown). [...] Importantly, we have documented that neither Tau nor the half-life of released DA are changed in slices from TAAR1-KO animals, indicating that TAAR1-KO mice exhibit unaltered DA uptake ability and thereby normal dopamine transporter (DAT) functionality. It is believed that Tau and the half-life of released DA are reliable measures for detecting changes in DA uptake because they are strongly correlated with changes in the Km of DAT mediated DA uptake (Yorgason et al., 2011). Thus, these neurochemical in vivo studies, as well as previous demonstrations of the functional activity of TAAR1 ligands in mice lacking the DAT (Sotnikova et al., 2004; Revel et al., 2012a), provide little support for the postulated role of TAAR1 in modulating DAT activity that is based mostly on in vitro cell culture experiments (Miller et al., 2005; Xie et al., 2008; Miller, 2011). [...] Importantly, we have documented that neither Tau nor the half-life of released DA are changed in slices from TAAR1-KO animals, indicating that TAAR1-KO mice exhibit unaltered DA uptake ability and thereby normal dopamine transporter (DAT) functionality. It is believed that Tau and the half-life of released DA are reliable measures for detecting changes in DA uptake because they are strongly correlated with changes in the Km of DAT mediated DA uptake (Yorgason et al., 2011). Thus, these neurochemical in vivo studies, as well as previous demonstrations of the functional activity of TAAR1 ligands in mice lacking the DAT (Sotnikova et al., 2004; Revel et al., 2012a), provide little support for the postulated role of TAAR1 in modulating DAT activity that is based mostly on in vitro cell culture experiments (Miller et al., 2005; Xie et al., 2008; Miller, 2011).
  8. 1 2 3 4 5 Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A. 108 (20): 8485–8490. Bibcode:2011PNAS..108.8485R. doi: 10.1073/pnas.1103029108 . PMC   3101002 . PMID   21525407. The endogenous TAAR1 agonist pTyr inhibits the firing frequency of DA neurons in the VTA, where Taar1 is expressed (10), whereas blockade of TAAR1 with EPPTB strongly increases their firing rate (17).
  9. 1 2 3 4 5 6 7 8 9 10 11 Zhang X, Mantas I, Alvarsson A, Yoshitake T, Shariatgorji M, Pereira M, Nilsson A, Kehr J, Andrén PE, Millan MJ, Chergui K, Svenningsson P (2018). "Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine". Front Pharmacol. 9: 166. doi: 10.3389/fphar.2018.00166 . PMC   5837966 . PMID   29545750.
  10. 1 2 Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID   18083911.
  11. 1 2 3 4 5 Wu R, Li JX (December 2021). "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs. 35 (12): 1239–1248. doi:10.1007/s40263-021-00871-4. PMC   8787759 . PMID   34766253. Similar to TYR, RO5166017 reduced the firing rate of VTA dopamine neurons and DRN serotonin neurons in brain slices from WT but not TAAR1-KO mice, through the activation of K+-mediated outward current, which can be blocked by TAAR1 antagonist EPPTB [38]. [...] Intriguingly, unlike TAAR1 full agonists, RO5203648 increased the firing frequency of VTA dopamine neurons and DRN serotonin neurons in vitro, similar to TAAR1 antagonist EPPTB [40]. [...] EPPTB—Currently, there is only one TAAR1 antagonist engineered for studying the role of TAAR1 in modulating the monoaminergic system. EPPTB was developed in 2009 by Bradaia and colleagues, and showed higher affinity to mouse TAAR1 than rat and human TAAR1 [81]. [...] EPPTB prevented the inhibition of firing frequency of dopamine neurons induced by non-selective TAAR1 agonist TYR in dopamine neurons of WT but not TAAR1-KO mice [81], suggesting a high selectivity. Given that TAAR1 has an inhibitory role in the dopaminergic system, which contributes to the alleviation of substance use disorder, the antagonism of TAAR1 may have minimal effects in drug addiction. However, it shows potential in preventing hypodopaminergic functions and thus may be useful for the treatment of disorders like Parkinson's disease [56].
  12. 1 2 3 Dedic N, Dworak H, Zeni C, Rutigliano G, Howes OD (December 2021). "Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies". Int J Mol Sci. 22 (24): 13185. doi: 10.3390/ijms222413185 . PMC   8704992 . PMID   34947997. Consistent with this, the firing rate of dopaminergic VTA neurons is increased in TAAR1-KO mice and enhanced by the TAAR1 antagonist EPPTB [72,84]. Interestingly, the partial agonists RO5203648 and RO5263397 also increase VTA DA neuron firing suggesting that, in vitro, TAAR1 is constitutively active and/or tonically activated by endogenous agonists, a situation where partial agonism produces a net antagonistic effect [74,111]. The extent to which such differential effects occur in vivo remains to be determined. [...] Similar to the findings in the VTA, full and partial agonists increase and decrease serotonergic neuronal firing in the DRN, respectively [74,86]. These effects were TAAR1- dependent as they were not observed in TAAR1-KO mice and reversed by the antagonist EPPTB [74,86].
  13. ↑ De Gregorio D, Enns JP, Nuñez NA, Posa L, Gobbi G (2018). "D-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders". Psychedelic Neuroscience. Progress in Brain Research. Vol. 242. pp. 69–96. doi:10.1016/bs.pbr.2018.07.008. ISBN   978-0-12-814255-4. PMID   30471683.{{cite book}}: |journal= ignored (help)
  14. ↑ De Gregorio D, Posa L, Ochoa-Sanchez R, McLaughlin R, Maione S, Comai S, Gobbi G (November 2016). "The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors". Pharmacol Res. 113 (Pt A): 81–91. doi:10.1016/j.phrs.2016.08.022. PMID   27544651.
  15. 1 2 Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (September 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur J Pharmacol. 763 (Pt B): 136–142. doi:10.1016/j.ejphar.2015.06.026. PMID   26093041.
  16. 1 2 Köhrle J, Biebermann H (April 2019). "3-Iodothyronamine-A Thyroid Hormone Metabolite With Distinct Target Profiles and Mode of Action". Endocr Rev. 40 (2): 602–630. doi:10.1210/er.2018-00182. PMID   30649231.
  17. 1 2 Halff EF, Rutigliano G, Garcia-Hidalgo A, Howes OD (January 2023). "Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders". Trends Neurosci. 46 (1): 60–74. doi:10.1016/j.tins.2022.10.010. PMID   36369028.
  18. ↑ Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ (November 2011). "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci. 31 (47): 16928–16940. doi:10.1523/JNEUROSCI.2502-11.2011. PMC   6623861 . PMID   22114263.
  19. 1 2 3 4 5 6 Liu J, Wu R, Seaman R, Manz KM, Johnson B, Vu J, Huang Y, Zhang Y, Robison AJ, Neve R, Grueter BA, Dietz D, Li JX (April 2022). "TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc". Mol Psychiatry. 27 (4): 2136–2145. doi:10.1038/s41380-022-01448-3. PMC   9829124 . PMID   35079125.
  20. ↑ Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC   3005101 . PMID   21073468.
  21. 1 2 Raony Í, Domith I, Lourenco MV, Paes-de-Carvalho R, Pandolfo P (July 2022). "Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD". Prog Neuropsychopharmacol Biol Psychiatry. 117: 110555. doi:10.1016/j.pnpbp.2022.110555. PMID   35346791.
  22. ↑ Kong Q, Zhang H, Wang M, Zhang J, Zhang Y (June 2021). "The TAAR1 inhibitor EPPTB suppresses neuronal excitability and seizure activity in mice". Brain Res Bull. 171: 142–149. doi:10.1016/j.brainresbull.2021.03.018. PMID   33811954.
  23. ↑ Landucci E, Gencarelli M, Mazzantini C, Laurino A, Pellegrini-Giampietro DE, Raimondi L (October 2019). "N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity". Neurochem Int. 129: 104460. doi:10.1016/j.neuint.2019.05.004. hdl:2158/1166895. PMID   31075293.
  24. ↑ Alexander L, Anderson D, Baxter L, Claydon M, Rucker J, Robinson ES (October 2024). "Preclinical models for evaluating psychedelics in the treatment of major depressive disorder". Br J Pharmacol. doi:10.1111/bph.17370. PMID   39467003.
  25. ↑ Shahar O, Botvinnik A, Esh-Zuntz N, Brownstien M, Wolf R, Lotan A, Wolf G, Lerer B, Lifschytz T (November 2022). "Role of 5-HT2A, 5-HT2C, 5-HT1A and TAAR1 Receptors in the Head Twitch Response Induced by 5-Hydroxytryptophan and Psilocybin: Translational Implications". Int J Mol Sci. 23 (22): 14148. doi: 10.3390/ijms232214148 . PMC   9698447 . PMID   36430623.
  26. 1 2 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.
  27. 1 2 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.
  28. ↑ Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP (October 2007). "The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia". Genes Brain Behav. 6 (7): 628–639. doi:10.1111/j.1601-183X.2006.00292.x. PMID   17212650.
  29. ↑ Scarano N, Espinoza S, Brullo C, Cichero E (July 2024). "Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands". Int J Mol Sci. 25 (15): 8226. doi: 10.3390/ijms25158226 . PMC   11312273 . PMID   39125796. On the other hand, HTS approaches [100] followed by structure-activity optimization allowed for the discovery of the hTAAR1 antagonist RTI-7470-44, endowed with a species-specificity preference over mTAAR1 (Figure 11A) [99]. RTI-7470-44 displayed good blood–brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. In addition, RTI-7470-44 increased the spontaneous firing rate of mouse ventral tegmental area (VTA) dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017. [...] Figure 11. (A) Chemical structures of the available hTAAR1 agonists: EPPTB [98], RTI-7470-44 [99], and 4c [33], [...] RTI-7470-44: hTAAR1 IC50 = 0.0084 μM, mTAAR1 IC50 = 1.190 μM.
  30. ↑ Zilberg G, Parpounas AK, Warren AL, Yang S, Wacker D (January 2024). "Molecular basis of human trace amine-associated receptor 1 activation". Nat Commun. 15 (1): 108. Bibcode:2024NatCo..15..108Z. doi:10.1038/s41467-023-44601-4. PMC   10762035 . PMID   38168118. Studies have shown that there are considerable functional and pharmacological differences between hTA1 and TA1 in rats (rTA1) or mice (mTA1)12, with key implications for translating findings from preclinical models into human therapies. For instance, TYR has been reported to be ~30 times more potent at rTA1 than hTA1, and the antagonist EPPTB was shown to have an affinity of ~1 nM at mTA1 but does not appear to bind hTA132. Inversely, the recently reported TA1 antagonist RTI-7470-44 has an IC50 of about 8 nM at hTA1 but shows ~90-fold and ~140-fold reduced potencies at rTA1 and mTA1, respectively33.
  31. ↑ Liu J, Wu R, Li JX (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther. 253: 108580. doi:10.1016/j.pharmthera.2023.108580. PMID   38142862. Similar to EPPTB, RTI-7470-44 could increase the spontaneous firing rate of dopaminergic neurons in mice VTA slices and prevent the effects of TAAR1 agonist RO5166017 (Decker et [...] Furthermore, RTI-7470-44 has appropriate properties for in vivo use, including favorable preliminary off-target profile, moderate metabolic stability, and good blood-brain barrier permeability [...] However, currently there is no behavioral study that investigated the effects of RTI-7470-44. Compared to the limited literature on TAAR1 antagonists, many TAAR1 agonists have been [...]


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