TAAR1

Discovery

The TAAR1 was discovered in 2001 by two independent groups, Borowski et al. and Bunzow et al.. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1. Further characterization of the functional role of TAAR1 and other receptors from this family was performed by other researchers including Raul Gainetdinov and his colleagues.

Structure

TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily. It has 7 transmembrane domains with short N and C terminal extensions. TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving. TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction.

Gene

All human TAAR genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons. The human TAAR1 gene is thought to be an intronless gene.

Tissue distribution

To date, TAAR1 has been identified and cloned in five different mammal genomes: human, mouse, rat, monkey, and chimpanzee. In rats, mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the stomach, kidney, intestines and lungs, and at low levels in the brain. Rhesus monkey Taar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of both species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus. hTAAR1 has also been identified in human astrocytes.

Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in the stomach, intestines, duodenum, pancreatic β-cells, and white blood cells. In the duodenum, TAAR1 activation increases glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) release; in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth hormone-inhibiting hormone) secretion from delta cells.

hTAAR1 is the only human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium.

Location within neurons

TAAR1 is a primarily intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals. In model cell systems, hTAAR1 has extremely poor membrane expression. A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.

Because TAAR1 is an intracellular receptor in monoamine neurons, exogenous TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux. Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron. The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons. E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal – markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.

A 2016 study found that most TAAR1 was expressed in intracellular membranes near the nucleus and that 2.3% of TAAR1 was expressed at the cell surface. In addition, TAAR1 signaling via the protein kinase A (PKA) pathway was predominantly associated with cell-surface TAAR1.

TAAR1 ligands have also been found to enter neurons by transporters other than the monoamine transporters.

Receptor oligomers

TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo. These and other reported TAAR1 hetero-oligomers include:

• TAAR1 D2sh
• TAAR1 α2A
• TAAR1 TAAR2 [note 2] in the TAAR1- D2sh example shows that TAAR1 can be located at cell membranes, and in the case of enterochromaffin cells in the gut epithelium, TAAR1 can be activated by high doses of dietary 'trace' amines, proximal to vesicles packed with catecholamines, impacting the vagal nerve system and CNS. This raises questions about where T1AM might find TAAR1 and cause similar unexpected nerve firing.

Ligands

Partial agonists: RO5203648, RO5263397, RO5073012, ralmitaront

Agonists

Endogenous

Main article: Trace amine#List of trace amines

The known endogenous agonists of the TAAR1 include trace amines like β-phenethylamine (PEA), monoamine neurotransmitters like dopamine, and thyronamines like 3-iodothyronamine (T1AM).

Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10nM in the brain, constituting less than 1% of total biogenic amines in the mammalian nervous system. Some of the human trace amines include tryptamine, phenethylamine (PEA), N-methylphenethylamine, p-tyramine, m-tyramine, N-methyltyramine, p-octopamine, m-octopamine, and synephrine. These share structural similarities with the three common monoamine neurotransmitters: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increased cyclic AMP (cAMP) concentration after the binding event. The rank order of potency for the primary endogenous ligands at the human TAAR1 is: tyramine β-phenethylamine dopamine= octopamine. Tryptamine and histamine also interact with the human TAAR1 with lower potency, whereas serotonin and norepinephrine have been found to be inactive.

Thyronamines are molecular derivatives of thyroid hormone involved in endocrine system function. 3-Iodothyronamine (T1AM) is one of the most potent TAAR1 agonists yet discovered. It also interacts with a number of other targets. Unlike the monoamine neurotransmitters and trace amines, T1A is not a monoamine transporter (MAT) substrate, although it does still weakly interact with the MATs. 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.

Other endogenous TAAR1 agonists include cyclohexylamine, isoamylamine, and trimethylamine, among others.

Exogenous

• 2-Aminoindanes
  • 2-Aminoindane (2-AI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 full agonist in humans
  • 5-Iodo-2-aminoindane (5-IAI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 partial agonist in humans
  • MDAI – a potent TAAR1 full agonist in rodents, weaker TAAR1 partial agonist in humans
  • N-Methyl-2-AI (NM-2-AI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 partial agonist in humans
• A-77636 – an experimental dopamine agonist
• Amphetamines (α-methyl-β-phenethylamines)
  • 4-Fluoroamphetamine – a potent TAAR1 partial agonist in rodents, but much less potent in humans
  • 4-Hydroxyamphetamine – an amphetamine metabolite
  • Amphetamine – a potent TAAR1 near-full agonist in rodents, but much less potent in humans
  • Cathinone – weak rodent and human TAAR1 partial agonist
  • MDA – a potent TAAR1 partial agonist in rodents, but much less potent weak partial agonist in humans
  • MDMA – a moderate-efficacy TAAR1 partial agonist in rodents, but much less potent weak partial agonist in humans
  • Methamphetamine – a potent TAAR1 near-full agonist in rodents, but much less potent in humans
  • Phentermine – a weak human TAAR1 near-full agonist
  • Selegiline (L-deprenyl) – a weak mouse TAAR1 partial agonist
  • Solriamfetol – a wakefulness-promoting agent acting as a dual norepinephrine–dopamine reuptake inhibitor (NDRI) and human TAAR1 agonist
• AP163 – a TAAR1 agonist
• Apomorphine – a dopamine agonist and antiparkinsonian agent, potent rodent TAAR1 agonist but not in humans
• Asenapine – an atypical antipsychotic
• Chlorpromazine – a dopamine antagonist and antipsychotic
• Clonidine – an adrenergic agonist and antihypertensive agent, rodent and human TAAR1 agonist
• Cyproheptadine – a serotonin antagonist
• Ergolines and lysergamides
  • Bromocriptine – a dopamine agonist and antiparkinsonian agent
  • Dihydroergotamine – an antimigraine agent
  • Ergometrine (ergonovine) – an obstetric drug
  • Lisuride – a dopamine agonist and antiparkinsonian agent
  • Lysergic acid diethylamide (LSD) – a serotonergic psychedelic and TAAR1 weak partial agonist in rodents but not in humans
  • Metergoline – a prolactin inhibitor
• Fenoldopam – a dopamine agonist and antihypertensive agent
• Fenoterol – an adrenergic agonist
• Guanabenz – an adrenergic agonist and antihypertensive agent, highly potent rodent and human TAAR1 agonist
• Guanfacine – an adrenergic agonist and ADHD medication
• Idazoxan – adrenergic antagonist, potent mouse TAAR1 agonist but much weaker in humans
• Isoprenaline – an adrenergic agonist
• LK00764 – a rodent and human TAAR1 agonist
• MPTP – a monoaminergic neurotoxin
• Naphazoline – an adrenergic agonist
• Nomifensine – a norepinephrine–dopamine reuptake inhibitor (NDRI) and abandoned antidepressant
• o-Phenyl-3-iodotyramine (o-PIT) – a rodent and human TAAR1 agonist
• Oxymetazoline – an adrenergic agonist
• Phentolamine – an adrenergic antagonist and rat TAAR1 agonist
• Ralmitaront (RG-7906, RO6889450) – a TAAR1 partial agonist and investigational antipsychotic
• RG-7351 – a TAAR1 partial agonist and abandoned experimental antidepressant
• RG-7410 – a TAAR1 agonist and abandoned experimental antipsychotic
• Ring-methoxylated phenethylamines and amphetamines
  • 2C-B – a serotonergic psychedelic, potent rat TAAR1 partial agonist but much weaker mouse and human TAAR1 partial agonist
  • 2C-E – a serotonergic psychedelic, potent rat TAAR1 partial agonist but much weaker mouse TAAR1 partial agonist and not in humans
  • 2C-T-7 – a serotonergic psychedelic, very high-affinity TAAR1 ligand in mice and rats but not in humans
  • DOB – a very weak human TAAR1 agonist
  • DOET – a weak human TAAR1 agonist
  • DOI – a rat TAAR1 agonist
  • DOM – a rhesus monkey TAAR1 agonist but not in humans
  • Mescaline – a serotonergic psychedelic, potent rodent TAAR1 partial agonist but not in humans
• RO5073012 – a selective rodent and human TAAR1 low-efficacy partial agonist
• RO5166017 – a selective rat and human TAAR1 near-full agonist but partial agonist in mice
• RO5203648 – a selective rodent and human TAAR1 partial agonist
• RO5256390 – a selective rat and human TAAR1 full agonist but partial agonist in mice
• RO5263397 – a selective rodent and human TAAR1 partial agonist
• S18616 – an adrenergic agonist
• Synephrine – an adrenergic agonist
• Tolazoline – an adrenergic antagonist and rat TAAR1 agonist
• Tryptamines
  • Dimethyltryptamine – a serotonergic psychedelic, TAAR1 partial agonist in rodents but not in humans
  • Psilocin – a serotonergic psychedelic, TAAR1 partial agonist in rodents but not in humans
• Ulotaront (SEP-363856, SEP-856) – a human TAAR1 full agonist and investigational antipsychotic

Although amphetamine, methamphetamine, and MDMA are potent TAAR1 agonists in rodents, they are less potent at human TAAR1. For example, based on TAAR1 activation EC50 values, amphetamine and methamphetamine show nanomolar potency at rodent TAAR1, but micromolar potency at human TAAR1. MDMA shows very low potency and efficacy as a human TAAR1 agonist and has been described as inactive. The magnitude of TAAR1-mediated effects of amphetamines in humans at low doses is uncertain. Given the micromolar EC50 values reported for human TAAR1, TAAR1 agonism may be more relevant at high recreational doses. TAAR1 activation can inhibit monoaminergic neuronal firing and is expected to reduce action potential-dependent (vesicular) monoamine release.

While some amphetamines are human TAAR1 agonists, many others are not. As examples, most cathinones (β-ketoamphetamines), such as methcathinone, mephedrone, and flephedrone, as well as other amphetamines, including ephedrine, 4-methylamphetamine (4-MA), para-chloroamphetamine (PCA), para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), MDEA, MBDB, 5-APDB, and 5-MAPDB, are inactive as human TAAR1 agonists. Many other drugs acting as monoamine releasing agents (MRAs) are also inactive as human TAAR1 agonists, for instance piperazines like benzylpiperazine (BZP), meta-chlorophenylpiperazine (mCPP), and 3-trifluoromethylphenylpiperazine (TFMPP), as well as the alkylamine methylhexanamine (DMAA). The negligible TAAR1 agonism with most cathinones might serve to enhance their effects and misuse potential as MRAs compared to their amphetamine counterparts.

Monoaminergic activity enhancers (MAEs), such as selegiline, benzofuranylpropylaminopentane (BPAP), and phenylpropylaminopentane (PPAP), have been claimed to act as TAAR1 agonists to mediate their MAE effects, but TAAR1 agonism for BPAP and PPAP has yet to be assessed or confirmed. Selegiline is only a weak agonist of the mouse TAAR1, with dramatically lower potency than amphetamine or methamphetamine, and does not seem to have been assessed at the human TAAR1.

Antagonists and inverse agonists

• Compound 22 – a very low-potency and non-selective TAAR1 antagonist
• EPPTB (RO5212773) – a selective mouse TAAR1 inverse agonist but far less potent rat and human TAAR1 neutral antagonist
• RTI-7470-44 – a potent and selective human TAAR1 neutral antagonist but far less potent mouse and rat TAAR1 antagonist

A few other less well-known TAAR1 antagonists have also been discovered and characterized.

RO5073012 is an antagonist-esque weak partial agonist of the rodent and human TAAR1 ( = 24–35%). Similarly, MDA and MDMA are weak to very weak partial agonists or antagonists of the human TAAR1 (Emax = 11% and 26%, respectively), albeit with very low potency.

It has been claimed that rasagiline may act as a TAAR1 antagonist, but TAAR1 interactions have yet to be assessed or confirmed for this agent.

Function

Monoaminergic systems

Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites. Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.

One of the downstream effects of active TAAR1 is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase. This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cell cytoplasm. These amines would then activate intracellular TAAR1. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons. As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.

In neurons with co-localized TAAR1, TAAR1 agonists can regulate monoamine concentrations in the synaptic cleft through effects on neuronal excitability and monoamine transporter function. Through direct activation of G protein-coupled inwardly-rectifying potassium channels (GIRKs), TAAR1 can reduce the firing rate of dopamine neurons, in turn preventing a hyper-dopaminergic state. Amphetamine and trace amines can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, these compounds activate can activate TAAR1 which, through protein kinase A (PKA), protein kinase C (PKC), and Ras Homolog family member A (RhoA) signaling, causes DAT phosphorylation.Activation of any these intracellular signaling pathways can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).

Electrophysiological studies have linked TAAR1 activation to reduced excitability of midbrain dopamine neurons, including increased spontaneous firing in TAAR1 gene knockout animals and TAAR1-dependent suppression of neuronal firing in wild-type tissue. A review noted that reduced VTA dopamine neuron firing would be expected to decrease extracellular dopamine, whereas TAAR1-mediated regulation of DAT function, including transporter internalization and reverse transport, would be expected to increase extracellular dopamine. To address comparatively limited work on whether TAAR1 agonists affect synaptic dopamine via DAT, a 2025 study on TAAR1-mediated regulation of transporter function compared amphetamine with three other TAAR1 agonists (RO5166017, RO5256390, and ulotaront) and reported that these TAAR1 agonists produce distinct effects on DAT function. In HEK 293T cells stably expressing human TAAR1 (hTAAR1) and human DAT (hDAT), RO5166017 and RO5256390 were shown to bind to hDAT and competively inhibited hDAT-mediated dopamine reuptake, whereas ulotaront did not show detectable hDAT binding. In the same cell system, RO5256390 and ulotaront reduced dopamine reuptake, while RO5166017 increased reuptake, and these reuptake changes were hTAAR1-dependent. RO5166017 increased hDAT expression at the plasma membrane and potentiated amphetamine-induced reverse transport in a hTAAR1-dependent manner, whereas RO5256390 and ulotaront did not alter amphetamine-induced hDAT efflux. The authors concluded that although these hTAAR1 agonists are relatively consistent in their effects on reducing VTA dopamine neuron firing, they are less consistent in effects on hDAT uptake and membrane expression, and only amphetamine induced hDAT-mediated dopamine efflux.

Immune system

Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics. In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades. In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system. A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.

Phytohaemagglutinin upregulates hTAAR1 mRNA in circulating leukocytes; in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists. TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells.

Astrocyte-localized TAAR1 regulates EAAT2 levels and function in these cells; this has been implicated in methamphetamine-induced pathologies of the neuroimmune system.

Clinical significance

Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, and high concentrations are associated with schizophrenia. Low PEA levels and under-activation of TAAR1 also appears to be associated with ADHD. It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression. Some antidepressants function by inhibiting monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells. Decreased PEA metabolism has been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function. Mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.

Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.). Despite wide distribution outside of the CNS and PNS, TAAR1 does not affect hematological functions and the regulation of thyroid hormones across different stages of ageing. Such data represent that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile.

Research

A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this possibly presents a target for therapeutic intervention.

In preclinical research on rats, TAAR1 activation in pancreatic cells promotes insulin, peptide YY, and GLP-1 secretion; therefore, TAAR1 is potentially a biological target for the treatment of obesity and diabetes.

Lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.

Notes

References

References

1. "Entrez Gene: TAAR1 trace amine associated receptor 1".
2. (July 2018). "Trace Amines and Their Receptors". Pharmacol Rev.
3. (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proceedings of the National Academy of Sciences of the United States of America.
4. (June 2018). "Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases". Expert Opin Ther Targets.
5. (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther.
6. (December 2001). "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Molecular Pharmacology.
7. "TAAR1". The Human Protein Atlas.
8. (December 2017). "Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges". Pharmacology & Therapeutics.
9. (2016). "Saturday Abstracts: 1012. Membrane Orientation, Cellular Localization and Signal Transduction of the Human Trace Amine-Associated Receptor 1". Biological Psychiatry.
10. (2022). "Behavioral Pharmacology of Drug Abuse: Current Status".
11. (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend..
12. (2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". Eur Neuropsychopharmacol.
13. (2016). "Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications". Front Neurosci.
14. (December 2006). "Trace amine-associated receptors and their ligands". British Journal of Pharmacology.
15. (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther.
16. (2017). "The Case for TAAR1 as a Modulator of Central Nervous System Function". Front Pharmacol.
17. (December 2016). "Thyronamines and Derivatives: Physiological Relevance, Pharmacological Actions, and Future Research Directions". Thyroid.
18. (June 2020). "3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors". Exp Clin Endocrinol Diabetes.
19. (June 2007). "Thyronamines inhibit plasma membrane and vesicular monoamine transport". ACS Chem Biol.
20. (December 2023). "Ligand recognition and G-protein coupling of trace amine receptor TAAR1". Nature.
21. (December 2007). "Trace amine-associated receptor 1-Family archetype or iconoclast?". Pharmacol Ther.
22. (December 2011). "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorg Med Chem.
23. (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Mol Pharmacol.
24. (October 2007). "The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia". Genes Brain Behav.
25. (2023). "Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion". CNS Spectrums.
26. (September 2022). "Discovery and In Vivo Efficacy of Trace Amine-Associated Receptor 1 (TAAR1) Agonist 4-(2-Aminoethyl)-N-(3,5-dimethylphenyl)piperidine-1-carboxamide Hydrochloride (AP163) for the Treatment of Psychotic Disorders". Int J Mol Sci.
27. (October 2014). "TAAR1-dependent effects of apomorphine in mice". Int J Neuropsychopharmacol.
28. (2024). "Unlocking the secrets of trace amine-associated receptor 1 agonists: new horizon in neuropsychiatric treatment". Front Psychiatry.
29. (September 2017). "Targeting species-specific trace amine-associated receptor 1 ligands: to date perspective of the rational drug design process". Future Med Chem.
30. (November 2023). "Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays". Pharmaceuticals.
31. (2011). "Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists". PLOS ONE.
32. (November 2022). "Discovery of Trace Amine Associated Receptor 1 (TAAR1) Agonist 2-(5-(4'-Chloro-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders". Biomolecules.
33. (February 2006). "Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues". J Med Chem.
34. (September 2023). "In Vitro Comparison of Ulotaront (SEP-363856) and Ralmitaront (RO6889450): Two TAAR1 Agonist Candidate Antipsychotics". Int J Neuropsychopharmacol.
35. (5 November 2023). "RG 7351". Springer Nature Switzerland AG.
36. (19 September 2024). "Delving into the Latest Updates on RG-7351 with Synapse".
37. (13 October 2015). "RG 7410".
38. (19 September 2024). "Delving into the Latest Updates on RG-7410 with Synapse".
39. (December 2021). "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs.
40. (May 2013). "A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight". Mol Psychiatry.
41. (October 2023). "Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia". Eur Arch Psychiatry Clin Neurosci.
42. (July 2023). "Unlocking the Therapeutic Potential of Ulotaront as a Trace Amine-Associated Receptor 1 Agonist for Neuropsychiatric Disorders". Biomedicines.
43. (March 2020). "TAAR Agonists". Cell Mol Neurobiol.
44. (April 2007). "Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine". J Pharmacol Exp Ther.
45. (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci.
46. (February 2016). ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend.
47. (2014). "Taste and Smell". Springer International Publishing.
48. (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol.
49. (January 2013). "Pharmacological characterization of designer cathinones in vitro". Br J Pharmacol.
50. (November 2011). "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci.
51. (August 2023). "The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization". J Pharmacol Exp Ther.
52. (August 2022). "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". Int J Mol Sci.
53. (August 2023). "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". Int J Mol Sci.
54. (2018). "Behavioral Effects of a Potential Novel TAAR1 Antagonist". Front Pharmacol.
55. (2015). "Discovery of trace amine-associated receptor 1 ligands by molecular docking screening against a homology model". MedChemComm.
56. (July 2024). "Computational Methods for the Discovery and Optimization of TAAR1 and TAAR5 Ligands". Int J Mol Sci.
57. (April 2022). "Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist". ACS Chem Neurosci.
58. (December 2014). "Further insights into the pharmacology of the human trace amine-associated receptors: discovery of novel ligands for TAAR1 by a virtual screening approach". Chem Biol Drug Des.
59. (January 2021). "Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1". SLAS Discov.
60. (November 2012). "Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine". Neuropsychopharmacology.
61. (August 2012). "Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012". Bioorg Med Chem Lett.
62. (2017). "The Case for TAAR1 as a Modulator of Central Nervous System Function". Frontiers in Pharmacology.
63. (2017). "The Case for TAAR1 as a Modulator of Central Nervous System Function". Frontiers in Pharmacology.
64. (2019). "Treatment strategies for ADHD: an evidence-based guide to select optimal treatment". Molecular Psychiatry.
65. (2025). "Trace amine-associated receptor 1 (TAAR1): an emerging therapeutic target for neurodegenerative, neurodevelopmental, and neurotraumatic disorders". Naunyn-Schmiedeberg's Archives of Pharmacology.
66. (2022). "Handbook of Substance Misuse and Addictions". Springer International Publishing.
67. (2022). "Handbook of Substance Misuse and Addictions". Springer International Publishing.
68. (September 2025). "Trace amine-associated receptor 1 agonists differentially regulate dopamine transporter function". Molecular Pharmacology.
69. (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci..
70. (August 2009). "Trace amine-associated receptors as emerging therapeutic targets". Mol. Pharmacol..
71. (January 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials.
72. (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol..
73. (March 2020). "Minimal Age-Related Alterations in Behavioral and Hematological Parameters in Trace Amine-Associated Receptor 1 (TAAR1) Knockout Mice". Cellular and Molecular Neurobiology.
74. (2016). "Incretin-like effects of small molecule trace amine-associated receptor 1 agonists". Mol Metab.
75. (May 2022). "Evaluation of Approach to a Conspecific and Blood Biochemical Parameters in TAAR1 Knockout Mice". Brain Sciences.
76. (March 2013). "Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2". Journal of Leukocyte Biology.
77. (September 2008). "Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor". Molecular Pharmacology.
78. (December 2019). "Actions of Trace Amines in the Brain-Gut-Microbiome Axis via Trace Amine-Associated Receptor-1 (TAAR1)". Cellular and Molecular Neurobiology.
79. (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.
80. (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology.
81. (June 2015). "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling". J. Mol. Endocrinol..
82. mct. (28 January 2012). "TAAR1". University of Paris.
83. (20 February 2018). "Trace amine receptor: TA₁ receptor". International Union of Basic and Clinical Pharmacology.
84. (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur. J. Pharmacol..
85. (2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Frontiers in Systems Neuroscience.
86. (August 2006). "A second class of chemosensory receptors in the olfactory epithelium". Nature.
87. (March 2005). "Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors". Genomics.
88. (March 2009). "International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature". Pharmacological Reviews.
89. (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry.
90. (December 2012). "Trace amine associated receptor 1 signaling in activated lymphocytes". Journal of Neuroimmune Pharmacology.
91. (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc. Natl. Acad. Sci. U.S.A..
92. (2012). "The molecular basis for neuroimmune receptor signaling". J Neuroimmune Pharmacol.
93. (February 2012). "Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia". Arthritis and Rheumatism.
94. (January 2007). "Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1". The Journal of Pharmacology and Experimental Therapeutics.
95. (April 2007). "Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro". The Journal of Pharmacology and Experimental Therapeutics.
96. (November 2009). "Trace amine-associated receptor 1 as a monoaminergic modulator in brain". Biochemical Pharmacology.
97. (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". The Journal of Pharmacology and Experimental Therapeutics.