Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders

Wü, Ray; Li, Jun-Xu

doi:10.1007/s40263-021-00871-4

Cited by 7 publications

(5 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, recent studies show that ATS can also activate the trace amine-associated receptor 1 (TAAR1), a G-protein-coupled receptor that negatively modulates the dopaminergic system and downregulates DAT expression. Interestingly, there is evidence that TAAR1 activation by a selective agonist reduces the reinforcing properties of psychostimulants 39,40 . These findings suggest that TAAR1 could be a potential therapeutic target to reduce the dopaminergic (and rewarding) effects of some ATS.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…These findings suggest that TAAR1 could be a potential therapeutic target to reduce the dopaminergic (and rewarding) effects of some ATS. Cathinones interact less with TAAR1 than AMPHs, which means that DAT remains on the cell surface contributing to monoamine release and increasing the risk of dependence 39 . Chronic ATS and binge administration (use of continuous high doses of psychostimulants over hours or days) produce long-lasting adaptive changes and damage to central dopaminergic and serotonergic neurons, particularly in the frontostriatal pathways.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

See 1 more Smart Citation

Amphetamine-type stimulants: Novel insights into their actions and use patterns

Paz-Ramos¹,

Cruz²,

Violante-Soria³

2023

RIC

View full text Add to dashboard Cite

This review focuses on the effects and mechanisms of action of amphetamine-type stimulants (ATS) and their adverse effects on the cardiovascular, nervous, and immune systems. ATS include amphetamine (AMPH), methamphetamine (METH, "crystalmeth," or "ice"), methylenedioxymethamphetamine (MDMA, "ecstasy," or "Molly"), MDMA derivatives (e.g., methylenedioxyamphetamine [MDA] and methylenedioxy-N-ethylamphetamine [MDEA]), khat, and synthetic cathinones. The first section of this paper presents an overview of the historical aspects of ATS use, their initial clinical use, and regulations. The second part reviews the acute and chronic impact and the most salient clinical effects of ATS on the central nervous and cardiovascular systems, skin, and mouth. The chemical structure, pharmacokinetics, and classic and non-canonical pharmacological actions are covered in the third section, briefly explaining the mechanisms involved. In addition, the interactions of ATS with the central and peripheral immune systems are reviewed. The last section presents data about the syndemic of ATS and opioid use in the North

show abstract

Section: Mechanisms Of Actionmentioning

confidence: 99%

Section: Mechanisms Of Actionmentioning

confidence: 99%

Amphetamine-type stimulants: Novel insights into their actions and use patterns

Paz-Ramos¹,

Cruz²,

Violante-Soria³

2023

RIC

View full text Add to dashboard Cite

show abstract

“…TAAR1, the most studied receptor subtype, is expressed in the stomach, central nervous system, kidney, lung, pancreas, prostate, spleen, skeletal muscle, heart, and leucocytes [4, 7]. TAAR1 is activated by RO5263397, a synthetic selective TAAR1 agonist [5, 8, 9]. The pharmacological actions of RO5263397 have been studied extensively in the central nervous system where it has been shown that RO5263397 modulated ethanol-induced behavioral sensitization and substance abuse disorders [10].…”

Section: Introductionmentioning

confidence: 99%

“…Batista-Lima et al [24] have reported that β-phenylethylamine, also a TAAR1 agonist, induced relaxation of the rat-isolated gastric fundus strip and that this relaxation was inhibited by the selective TAAR1 antagonist EPPTB (50 µ m ), possibly suggesting mediation of the relaxation response via TAAR1 [25]. However, in the same preparation, relaxation induced by RO5263397, a synthetic selective TAAR1 agonist [5, 8, 9], was not inhibited by EPPTB at the same concentration (50 µ m ) that significantly reduced octopamine- and phenylethylamine-induced relaxation, possibly indicating subtypes of TAAR1 [11, 24]. The main objective of this study was to investigate a possible vasodilator effect of TAAR1 agonists, RO5263397 (synthetic) and T1AM (endogenous), in the isolated perfused rat kidney.…”

Section: Introductionmentioning

confidence: 99%

Vasodilator Effect of Trace Amines, 3-Iodothyronamine, and RO5263397 in the Rat Perfused Kidney: Comparison with Tryptamine

Jragh¹,

Chandrasekhar²,

Yousif³

et al. 2023

Pharmacology

View full text Add to dashboard Cite

Introduction: Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors and are widely distributed in the body. Activation of TAAR1 by specific agonists can produce a variety of physiological effects centrally and peripherally. The objective of this study was to investigate the vasodilator effect of two selective TAAR1 agonists 3-iodothyronamine (T1AM) and RO5263397 in the isolated perfused rat kidney preparation. Methods: Kidneys were isolated and perfused with Krebs’ solution, gassed with 95% oxygen and 5% carbon dioxide, through the renal artery. Results: In preparations pre-constricted with methoxamine (5 × 10−6<sc>m</sc>), T1AM (10−10 – 10−6 mol), RO5263397 (10−10 – 10−6 mol), and tryptamine (10−10 – 10−6 mol) produced dose-dependent vasodilator responses. EPPTB (1 × 10−6<sc>m</sc>), a selective TAAR1 antagonist, had no effect on vasodilator responses induced by these agonists. A higher concentration of EPPTB (3 × 10−5<sc>m</sc>) produced a sustained increase in perfusion pressure but did not affect vasodilator responses to tryptamine, T1AM, and RO5263397. Agonist-induced vasodilator responses were slightly reduced by the removal of the endothelium but were not affected by L-NAME (1 × 10−4<sc>m</sc>), an inhibitor of nitric oxide synthesis. The vasodilator responses were significantly reduced by inhibiting calcium-activated (tetraethylammonium, 1 × 10−3<sc>m</sc>) and voltage-activated (4-AP, 1 × 10−3<sc>m</sc>) potassium channels. Tryptamine-, T1AM-, and RO5263397-induced vasodilator responses were significantly reduced by BMY7378, a 5-HT1A receptor antagonist. Conclusion: It was concluded that vasodilator responses produced by the TAAR1 agonists, T1AM, RO5263397, and tryptamine, were not mediated via TAAR1 but were probably via activation of 5-HT1A receptors.

show abstract

“…Trace amine-associated receptor 1 (TAAR1) is a promising target for the development of innovative therapies for many diseases, in virtue of its wide distribution in the brain and in diverse peripheral tissues [1][2][3][4][5]. TAAR1 is responsive to a class of biogenic compounds called trace amines (TAs), such as tyramine (TYR), β-phenylethylamine (β-PEA), and 3iodothyronamine (T1AM), whose dysregulation was correlated to the etiology of various diseases, like schizophrenia, depression, attention deficit hyperactivity disorder, substance abuse, metabolic syndrome, and Parkinson's disease [3,[6][7][8][9][10][11]. In the brain, TAAR1 proved to be an important modulator of the major monoamine (dopamine and serotonin) and glutamate signaling pathways, directing the attention of researchers on the therapeutic implications of TAAR1 ligands in neuropsychiatric disorders [3,12,13].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

Cichero,

Francesconi,

Casini

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation.

show abstract

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders

Cited by 7 publications

References 84 publications

Amphetamine-type stimulants: Novel insights into their actions and use patterns

Amphetamine-type stimulants: Novel insights into their actions and use patterns

Vasodilator Effect of Trace Amines, 3-Iodothyronamine, and RO5263397 in the Rat Perfused Kidney: Comparison with Tryptamine

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

Contact Info

Product

Resources

About