New insights into the structure of the trace amine‐associated receptor 2: Homology modelling studies exploring the binding mode of 3‐iodothyronamine

Recent studies have further investigated the trace amine‐associated receptor type 2 (TAAR2) pharmacology, revealing its role not only at the olfactory sensory neurons but also at the immune system, being expressed in human leucocytes. In particular, the ability of this receptor to bind the unselective TAAR ligand 3‐iodo‐thyronamine ( T ₁ AM ) was elucidated, making in the meanwhile the discovery of selective compounds a urgent need to derive much more suitable tools for studying TAARs. In this context, we developed our work on TAAR2 applying a structure‐based computational protocol, including TAAR2 homology modelling and T ₁ AM docking studies. The results were compared with those we previously obtained about TAAR1, in order to point out new insights guiding for selectivity between TAAR1 and TAAR2. The in silico strategy applied allowed us to provide for the first time thorough TAAR2 homology models, which are expected to be useful tools for a further design process of more selective TAAR ligands.     

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.     

Insights into the Structure and Pharmacology of the Human Trace Amine‐Associated Receptor 1 (hTAAR1): Homology Modelling and Docking Studies

Trace amine‐associated receptor 1 (TAAR1) is a G protein–coupled receptor that belongs to the family of TAAR receptors and responds to a class of compounds called trace amines, such as β‐phenylethylamine ( β‐PEA ) and 3‐iodothyronamine ( T ₁ AM ). The receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson’s disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein–agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein‐binding site has been explored by comparing the hTAAR1 model with the β₂‐adrenoreceptor binding site, available by X‐ray crystallization studies, and with the homology modelled 5HT_1A receptor. The obtained results, in tandem with docking studies performed with RO5166017 , β‐PEA and T ₁ AM , provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.     

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2 h apart, of MA (2.5, 5, or 10 mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7 days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5 mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects.     

Synephrine: From trace concentrations to massive consumption in weight-loss

Synephrine is cited as ‘the active component’ of plants and dietary supplements used in weight loss. It became one of the most popular stimulants present in weight-loss products after the US Food and Drug Administration had interdicted the use of ephedrine-containing dietary supplements. Synephrine is also a trace amine that can be found in vertebrates and invertebrates. Synephrine acts on several adrenergic and serotonergic receptors and its activity on trace-amine-associated receptors has long been discussed. Synephrine exists in three different positional isomers; however, only p- and m-synephrine have been described in weight-loss products. The alleged effectiveness of synephrine-containing supplements is attributed to the thermogenic effects arising from synephrine’s adrenergic stimulation. The growing use of synephrine has raised concerns since it has been accompanied by reports of adverse effects. Cardiac adverse events, including hypertension, tachyarrhythmia, variant angina, cardiac arrest, QT prolongation, ventricular fibrillation, myocardial infarction, and sudden death, have been the most common adverse effects associated with synephrine intake. The mechanisms involved in synephrine-induced cardiotoxicity are still unknown since studies related to its safety are scarce. This review will address general aspects concerning the pharmacology of synephrine, but will focus on the efficacy and toxicity aspects related to the use of synephrine in weight-loss.     

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

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