3-Iodothyronamine

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3-Iodothyronamine
3-Iodothyronamine.svg
3-Iodothyronamine 3D ball.png
Names
Preferred IUPAC name
4-[4-(2-Aminoethyl)-2-iodophenoxy]phenol
Other names
T1AM; o-(4-Hydroxyphenyl)-3-iodotyramine; 4′-Hydroxy-o-PIT
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.211.501 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
  • InChI=1S/C14H14INO2/c15-13-9-10(7-8-16)1-6-14(13)18-12-4-2-11(17)3-5-12/h1-6,9,17H,7-8,16H2 Yes check.svgY
    Key: XIINYOJWNGOUPF-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C14H14INO2/c15-13-9-10(7-8-16)1-6-14(13)18-12-4-2-11(17)3-5-12/h1-6,9,17H,7-8,16H2
    Key: XIINYOJWNGOUPF-UHFFFAOYAJ
  • OC1=CC=C(OC2=C(I)C=C(CCN)C=C2)C=C1
  • Ic2cc(ccc2Oc1ccc(O)cc1)CCN
Properties
C14H14INO2
Molar mass 355.17 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

3-Iodothyronamine (T1AM) is an endogenous thyronamine. It is a high-affinity ligand of the trace amine-associated receptor 1 (TAAR1). [1] [2] T1AM is the most potent endogenous TAAR1 agonist yet discovered. [3] 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). [4] [5] T1AM is not a ligand of the thyroid hormone receptors. [4] However, it is additionally a ligand of various monoamine and other receptors. [6] For instance, it is a muscarinic acetylcholine receptor antagonist. [7]

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. [8] 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. [3] T1AM may be part of a signaling pathway to modulate cardiac function, as the compound can induce negative inotropic effects and decrease cardiac output. [9]

T1AM has been found to produce TAAR1-dependent tyrosine hydroxylase (TH) phosphorylation in mouse dorsal striatum slices. [10] [6] This phosphorylation would be expected to promote the functional activity of TH. [10] [6] Accordingly, higher rates of L-DOPA accumulation were observed after administration of T1AM in mice treated with a DOPA decarboxylase inhibitor. [10] [6] The preceding effects were absent with TAAR1 knockout mice or with the TAAR1 antagonist EPPTB. [6] In addition, T1AM-mediated TH phosphorylation appeared to be mediated by CaMKII and protein kinase A (PKA) signaling. [10] [6] 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. [6] 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. [10] [6]

T1AM had no effect on locomotor activity in rodents at low doses but produced hypolocomotion at high doses. [11] [12]

See also

Related Research Articles

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<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.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

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

Thyronamine refers both to a molecule, and to derivatives of that molecule: a family of decarboxylated and deiodinated metabolites of the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3).

<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.

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors, are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine. In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones. TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.

<span class="mw-page-title-main">TAAR2</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene. TAAR2 is co-expressed with Gα proteins; however, as of February 2017, its signal transduction mechanisms have not been determined.

<span class="mw-page-title-main">TAAR5</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 5 is a protein that in humans is encoded by the TAAR5 gene. In vertebrates, TAAR5 is expressed in the olfactory epithelium.

<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.

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

3-Methoxytyramine (3-MT), also known as 3-methoxy-4-hydroxyphenethylamine, is a human trace amine and the major metabolite of the monoamine neurotransmitter dopamine. It is formed by the introduction of a methyl group to dopamine by the enzyme catechol-O-methyltransferase (COMT). 3-MT can be further metabolized by the enzyme monoamine oxidase (MAO) to form homovanillic acid (HVA), which is then typically excreted in the urine.

<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.

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

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 agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist 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.

<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 (TAAR1). 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. Its EC50Tooltip half-maximal effective concentration values have been reported to be 35 nM for the mouse TAAR1, 2.4 nM at the rat TAAR1, and 9.5 nM at the human TAAR1.

<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">RO5256390</span> Chemical compound

RO5256390 or RO-5256390 is a drug developed by Hoffmann-La Roche which acts as an agonist for the trace amine associated receptor 1 (TAAR1). It is a full agonist of the rat, cynomolgus monkey, and human TAAR1, but a partial agonist of the mouse TAAR1.

<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 or full agonist which is used in scientific research. It is the most well-studied of all of the synthetic TAAR1 ligands. In addition to its use in research, RO5263397 is or was under development for potential clinical use as a medication.

<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.

<span class="mw-page-title-main">RO5073012</span> Pharmaceutical compound

RO5073012 is a selective low-efficacy partial agonist of the trace amine-associated receptor 1 (TAAR1) which has been used in scientific research. TAAR1 partial agonists like RO5073012 can have agonist- or antagonist-like effects at the TAAR1 depending on the context and level of TAAR1 signaling.

References

  1. ↑ Scanlan T, Suchland K, Hart M, Chiellini G, Huang Y, Kruzich P, Frascarelli S, Crossley D, Bunzow J, Ronca-Testoni S, Lin E, Hatton D, Zucchi R, Grandy D (2004). "3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone". Nat. Med. 10 (6): 638–42. doi:10.1038/nm1051. PMID   15146179. S2CID   2389946.
  2. ↑ Hart M, Suchland K, Miyakawa M, Bunzow J, Grandy D, Scanlan T (2006). "Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues". J. Med. Chem. 49 (3): 1101–12. doi:10.1021/jm0505718. PMID   16451074.
  3. 1 2 Wu SY, Green WL, Huang WS, Hays MT, Chopra IJ (2005). "Alternate Pathways of Thyroid Hormone Metabolism". Thyroid. 15 (8): 943–958. doi:10.1089/thy.2005.15.943. PMID   16131336.
  4. 1 2 Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomed Pharmacother. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID   27424325.
  5. ↑ Dinter J, Mühlhaus J, Wienchol CL, Yi CX, Nürnberg D, Morin S, Grüters A, Köhrle J, Schöneberg T, Tschöp M, Krude H, Kleinau G, Biebermann H (2015). "Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5". PLOS ONE. 10 (2): e0117774. Bibcode:2015PLoSO..1017774D. doi: 10.1371/journal.pone.0117774 . PMC   4382497 . PMID   25706283.
  6. 1 2 3 4 5 6 7 8 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. In this study, we investigated the action of T1AM at TAAR1 on dopaminergic terminals as compared to those of TAs. However, T1AM is also known to be an agonist of TAAR5 (Dinter et al., 2015c). Moreover, the β-phenylethylamine-like structure affords T1AM the ability to bind with various members of GPCR superfamily and ion channels (Chiellini et al., 2017; Khajavi et al., 2017). It is indeed claimed that T1AM interacts with α2a adrenergic receptors, β2-adrenergic receptors and muscarinic receptors (Kleinau et al., 2011; Dinter et al., 2015a,b; Laurino et al., 2016, 2017). Notably, outside the CNS, T1AM has been found to differentially regulate insulin secretion through actions at TAAR1 and α2a adrenergic receptor (Chiellini et al., 2017; Lehmphul et al., 2017). Hence, despite blockade of the actions of T1AM in KO mice and by pharmacological antagonist, the possibility that it exerts actions via other mechanisms should not be excluded.
  7. ↑ Laurino A, Matucci R, Vistoli G, Raimondi L (December 2016). "3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors". Eur J Pharmacol. 793: 35–42. doi:10.1016/j.ejphar.2016.10.027. PMID   27815171.
  8. ↑ "New compound may act to keep thyroid activity in check" . Retrieved 2008-05-30.
  9. ↑ Chiellini G, Frascarelli S, Ghelardoni S, Carnicelli V, Tobias SC, Debarber A, Brogioni S, Ronca-Testoni S, Cerbai E, Grandy DK, Scanlan TS, Zucchi R (2007). "Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function". The FASEB Journal. 21 (7): 1597–608. doi: 10.1096/fj.06-7474com . PMID   17284482. S2CID   14015560.
  10. 1 2 3 4 5 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. One way in which TAAR1 regulates presynaptic dopamine function is by modulating phosphorylation levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis [59]. TH phosphorylation on serine (Ser) residues Ser19 [calmodulin-dependent protein kinase II (CaMKII)-targeted], Ser31 and Ser40 (PKA-targeted) determines its activity, and Ser40 phosphorylation is thought to be the main contributor to increasing TH activity and consequently dopamine production [60,61]. [...] TAAR1-KO mice display increased levels of phosphorylated TH at all three sites as well as elevated TH activity in the striatum, despite no change in overall TH protein or mRNA levels in this region [41]. [...] The TAs tyramine and PEA decrease Ser40 phosphorylation in mouse dorsal striatum, whereas 3-iodothyronamine (T1AM) increases TH phosphorylation at Ser19 and Ser40, as well as the production of the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) [63]. Endogenous T1AM, however, is only found in the periphery, and its role in TAAR1 function in the brain is therefore unclear [63]. The TAAR1 antagonist EPPTB reduces CaMKII activity in the nucleus accumbens (NAc), but TH phosphorylation was not investigated in this study, and it therefore remains unclear what effect antagonism has on TH [64].
  11. ↑ Piehl S, Hoefig CS, Scanlan TS, Köhrle J (February 2011). "Thyronamines--past, present, and future". Endocr Rev. 32 (1): 64–80. doi:10.1210/er.2009-0040. PMID   20880963. Intraperitoneal or icv injection of low doses of 3-T1AM (4 and 1.2 mol/kg body weight, respectively) into rats or mice caused a significant increase in food intake without affecting oxygen consumption and locomotor activity. However, at high 3-T1AM doses (50 mg/kg body weight, 127 mol), the authors confirmed the previously reported reduction of oxygen consumption and locomotor activity (3).
  12. ↑ Dhillo WS, Bewick GA, White NE, Gardiner JV, Thompson EL, Bataveljic A, Murphy KG, Roy D, Patel NA, Scutt JN, Armstrong A, Ghatei MA, Bloom SR (March 2009). "The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents". Diabetes Obes Metab. 11 (3): 251–260. doi:10.1111/j.1463-1326.2008.00935.x. PMID   18671794.
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