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MORE →Reflects the personal views, recollections, and perspective of the author, Mike Davis.
This is a personal recollection on the Move fire on May 13, 1985
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| Other names | Ro 5212773; Ro-5212773; Ro5212773; RO-5212773; RO5212773 |
| Drug class | Trace amine-associated receptor 1 (TAAR1) antagonist or inverse agonist |
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| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C20H21F3N2O2 |
| Molar mass | 378.395 g·mol−1 |
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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][4] The drug was the first selective antagonist developed for the TAAR1.[2][3] It is a potent antagonist of the mouse and rat TAAR1, but is dramatically less potent as an antagonist of the human TAAR1.[5][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]
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.[6]
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.[5][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][5]
| Species | Affinity (Ki, nM) | IC50 (nM) | Emax (%) |
|---|---|---|---|
| Mouse | 0.9 | 27.5 | –12% |
| Rat | 942 | 4,539 | 0% |
| Human | >5,000 | 7,487 | 0% |
EPPTB has no known significant activity at other targets besides the TAAR1.[2][3]
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][7][2][8][9] Similarly, EPPTB enhances electrically evoked dopamine release in nucleus accumbens (NAcc) but not dorsal striatum (DStr) slices ex vivo.[8] However, despite the increased dopamine neuron firing rates, basal extracellular dopamine levels in the striatum were not enhanced in TAAR1 knockout mice.[10][11] 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.[12][2][8][9] EPPTB blocked the suppression of DRN serotonin neuron firing by tyramine and RO5166017 as well.[13][9] The preceding effects of EPPTB were absent in slices from TAAR1 knockout mice.[1][2][8] 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).[14][1][15] 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.[12][16][2][9]
The TAAR1 partial agonists RO5203648 and RO5263397 enhance the firing rates of dopamine and serotonin neurons in brain slices ex vivo.[7][13] These findings suggest that the TAAR1 is constitutively and/or tonically active and that TAAR1 partial agonists produce net antagonism.[7][13] 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.[12][7]
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.[17][18] This was interpreted as possible support for TAAR1 agonism mediating psychostimulant-like effects of amphetamines.[17][18] 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.[19]
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.[20][21][10] This effect involved CaMKII and PKA activation.[20][10] In accordance with the enhanced expected TH activity, higher L-DOPA accumulation was observed in animals treated with T1AM and a DOPA decarboxylase inhibitor.[21][10] These effects of T1AM were abolished by TAAR1 knockout and by EPPTB.[10] In accordance with the preceding findings, T1AM also enhanced electrically evoked dopamine release in DStr slices ex vivo.[10] This effect was likewise reduced by TAAR1 knockout and by EPPTB.[10] By itself, EPPTB had no effect on evoked dopamine release in DStr slices ex vivo.[10] The preceding findings conflict with previous results that TAAR1 signaling inhibits the firing rates of VTA dopamine neurons.[10] These differing findings may be related to differential regulation of dopaminergic signaling in the VTA versus the DStr as well as other factors.[10] 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.[10][22]
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.[12] Relatedly, systemic or intra-NAcc shell administration of the TAAR1 agonist RO5166017 reduced drug-induced reinstatement of cocaine-seeking in rats and prevented drug priming-induced CaMKIIα activation in the NAcc shell.[23] CaMKIIα was inhibited but PKA, PKC, ERK1/2, CREB, or GSK3β were unaffected in NAcc slices from rats administered RO5166017.[23] The behavioral effects were blocked by viral expression of CaMKIIα in the NAcc shell.[23] In contrast to RO5166017, injection of EPPTB into the NAcc shell augmented drug-induced reinstatement of cocaine-seeking and enhanced CAMKIIα activity.[23]
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).[8] 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.[8][24] 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.[16][2] Likewise, EPPTB reduced the desensitization rate of serotonin 5-HT1A receptors in DRN slices ex vivo.[9]
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.[23][25] Similarly, locomotion is unchanged in TAAR1 knockout mice.[11] In contrast to EPPTB, TAAR1 agonists show anxiolytic or anxiogenic effects in different studies as well as hypolocomotive effects.[23][25] EPPTB has shown anticonvulsant[26] and neuroprotective effects in preclinical research.[27] EPPTB has been found to reduce the 5-hydroxytryptophan (5-HTP)-induced but not psilocybin-induced head-twitch response (HTR) in rodents.[28][29]
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.[30][31] Selegiline is a weak mTAAR1 agonist in vitro.[32] In relation to the preceding, it has been hypothesized that the effects of MAEs may be mediated by TAAR1 agonism.[30][31]
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).[5][3] Systemic administration produces centrally mediated effects in animals.[5] However, the drug has high clearance, and this has limited its research usefulness.[5][3]
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][12] 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.[33][34][35][5]
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).
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
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.
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).
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).
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].
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].
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[...] EPPTB's effect on the spontaneous locomotor activity in a familiar environment displayed by WT and taar1-deficient mice chronically exposed to 3 mg/kg METH (i.p.) over a range of doses was examined. The results of this study (Grandy, 2014; SfN abstracts) support the interpretation that EPPTB prevents to a significant degree METH-stimulated locomotor activity but only in WT mice with a history of chronic METH exposure.
The TAAR1-selective antagonist EPPTB blocked methamphetamine- and bupropion-stimulated chloride conductance in Xenopous oocytes co-expressing mouse TAAR1 and the human cystic fibrosis transmembrane conductance regulator in a concentration-dependent manner with IC50's of 2.3±0.3nM and 4.3±0.7nM, respectively. [...] EPPTB displayed no affinity for mouse biogenic amine transporters nor did it produce a significant phenotype in wildtype or taar1-/- mice. In contrast, at the highest dose tested (100 mg/kg, i.p.) EPPTB inhibited approximately 70% of methamphetamine-stimulated (3 mg/kg, i.p.) activity in wildtype mice while having no effect on similarly treated [TAAR1] knockout mice. Intraperitoneal co-administration of methamphetamine (3 mg/kg) and bupropion (50 mg/kg) to wildtype mice produced greater activity than either drug alone, an effect absent from [TAAR1] knockout mice. [...] The existence of a methamphetamine-activated G protein-coupled receptor that is also activated by bupropion [...]
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.
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.
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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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 antagonist of the mouse and rat TAAR1, but is dramatically less potent as an antagonist 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.
3-Iodothyronamine (T1AM) is an endogenous thyronamine. It is a high-affinity ligand of the trace amine-associated receptor 1 (TAAR1). T1AM is the most potent endogenous TAAR1 agonist yet discovered. It is also an agonist of the TAAR2 and TAAR5 with similar potency as for the TAAR1 (all in the case of the human proteins). T1AM is not a ligand of the thyroid hormone receptors. However, it is additionally a ligand of various monoamine and other receptors. For instance, it is a muscarinic acetylcholine receptor antagonist. Activation of TAAR1 by T1AM results in the production of large amounts of cyclic adenosine monophosphate (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. T1AM may be part of a signaling pathway to modulate cardiac function, as the compound can induce negative inotropic effects and decrease cardiac output. T1AM has been found to produce TAAR1-dependent tyrosine hydroxylase (TH) phosphorylation in mouse dorsal striatum slices. This phosphorylation would be expected to promote the functional activity of TH. Accordingly, higher rates of L-DOPA accumulation were observed after administration of T1AM in mice treated with a DOPA decarboxylase inhibitor. The preceding effects were absent with TAAR1 knockout mice or with the TAAR1 antagonist EPPTB. In addition, T1AM-mediated TH phosphorylation appeared to be mediated by CaMKII and protein kinase A (PKA) signaling. T1AM was also found to increase electrically evoked dopamine release in striatal slices, which was blunted in TAAR1 knockout mice and in mice treated with EPPTB, indicating partial mediation by the TAAR1. In contrast to T1AM, the trace amines β-phenethylamine and tyramine reduced TH phosphorylation, which was independent of the TAAR1, and hence do not appear to augment TH functional activity. T1AM had no effect on locomotor activity in rodents at low doses but produced hypolocomotion at high doses.
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 a primarily intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (CNS). TAAR1 is one of six functional human TAARs, 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. Endogenous ligands of the TAAR1 include trace amines, monoamine neurotransmitters, and certain thyronamines. The trace amines β-phenethylamine, tyramine, tryptamine, and octopamine, the monoamine neurotransmitters dopamine and serotonin, and the thyronamine 3-iodothyronamine (3-IT) are all agonists of the TAAR1 in different species. Other endogenous agonists are also known. A variety of exogenous compounds and drugs are TAAR1 agonists as well, including various phenethylamines, amphetamines, tryptamines, and ergolines, among others. There are marked species differences in the interactions of ligands with the TAAR1, resulting in greatly differing affinities, potencies, and efficacies of TAAR1 ligands between species. Many compounds that are TAAR1 agonists in rodents are much less potent or inactive at the TAAR1 in humans. A number of selective TAAR1 ligands have been developed, for instance the TAAR1 full agonist RO5256390, the TAAR1 partial agonist RO5263397, and the TAAR1 antagonists EPPTB and RTI-7470-44. Selective TAAR1 agonists are used in scientific research, and a few TAAR1 agonists, such as ulotaront and ralmitaront, are being developed as novel pharmaceutical drugs, for instance to treat schizophrenia and substance use disorder.
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. MAEs have been shown to significantly enhance nerve impulse-mediated dopamine release in the striatum, substantia nigra, and olfactory tubercle; norepinephrine release from the locus coeruleus; and/or serotonin release from the raphe nucleus in rodent studies. Some MAEs are selective for effects on some of these neurotransmitters but not on others. The maximal impacts of MAEs on brain monoamine levels are more modest than with monoamine releasing agents like amphetamine and monoamine reuptake inhibitors like methylphenidate. MAEs have a peculiar and characteristic bimodal concentration–response relationship, with two bell-shaped curves of MAE activity across tested concentration ranges. Hence, there is a restricted concentration range for optimal pharmacodynamic activity. Endogenous MAEs include certain trace amines like β-phenylethylamine and tryptamine, while synthetic MAEs include certain phenethylamine and tryptamine derivatives like selegiline, phenylpropylaminopentane (PPAP), benzofuranylpropylaminopentane (BPAP), and indolylpropylaminopentane (IPAP). Although this was originally not known, the actions of MAEs may be mediated by agonism of the trace amine-associated receptor 1 (TAAR1). Antagonists of MAEs, like EPPTB (a known TAAR1 antagonist), 3-F-BPAP, and rasagiline, have been identified. In 2025, it was discovered that PPAP is a potent catecholamine reuptake inhibitor, including of dopamine and to a lesser extent of norepinephrine.
Before the 1921 destruction of Tulsa’s Greenwood District, Black residents had created a remarkable center of business and community life. The district included stores, professional offices, entertainment venues and homes owned by Black citizens. Understanding Greenwood means learning what was built—not only what was burned.
MORE →Mae Jemison, aboard Space Shuttle Endeavour in 1992.
