3-Iodothyronamine

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{{Chembox

| Verifiedfields = changed

| verifiedrevid = 477219003

| ImageFile = 3-Iodothyronamine.svg

| ImageSize = 230px

| ImageAlt = Skeletal formula of the 3-iodothyronamine

| ImageFile1 = 3-Iodothyronamine 3D ball.png

| ImageSize1 = 230px

| ImageAlt1 = Ball-and-stick model of the 3-iodothyronamine molecule

| PIN = 4-[4-(2-Aminoethyl)-2-iodophenoxy]phenol

| OtherNames = T₁AM; o-(4-Hydroxyphenyl)-3-iodotyramine; 4′-Hydroxy-o-PIT

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 8126125

| PubChem = 9950514

| 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

| InChIKey = XIINYOJWNGOUPF-UHFFFAOYAJ

| SMILES1 = Ic2cc(ccc2Oc1ccc(O)cc1)CCN

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = XIINYOJWNGOUPF-UHFFFAOYSA-N

| CASNo_Ref = {{cascite|changed|??}}

| CASNo = 712349-95-6

| SMILES = OC1=CC=C(OC2=C(I)C=C(CCN)C=C2)C=C1

}}

|Section2={{Chembox Properties

| Formula = C₁₄H₁₄INO₂

| MolarMass = 355.17 g/mol

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|Section3={{Chembox Hazards

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3-Iodothyronamine (T₁AM) is an endogenous thyronamine. It is a high-affinity ligand of the trace amine-associated receptor 1 (TAAR1).{{cite journal |vauthors =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 |title=3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone |journal=Nat. Med. |volume=10 |issue=6 |pages=638–42 |year=2004 |pmid=15146179 |doi=10.1038/nm1051|s2cid=2389946 }}{{cite journal |vauthors =Hart M, Suchland K, Miyakawa M, Bunzow J, Grandy D, Scanlan T |title=Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues |journal=J. Med. Chem. |volume=49 |issue=3 |pages=1101–12 |year=2006 |pmid=16451074 |doi=10.1021/jm0505718}} T₁AM is the most potent endogenous TAAR1 agonist yet discovered.{{Cite journal | vauthors = Wu SY, Green WL, Huang WS, Hays MT, Chopra IJ | doi = 10.1089/thy.2005.15.943 | title = Alternate Pathways of Thyroid Hormone Metabolism | journal = Thyroid | volume = 15 | issue = 8 | pages = 943–958 | year = 2005 | pmid = 16131336 }} 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).{{cite journal | vauthors = 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 | title = Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5 | journal = PLOS ONE | volume = 10 | issue = 2 | pages = e0117774 | date = 2015 | pmid = 25706283 | pmc = 4382497 | doi = 10.1371/journal.pone.0117774 | doi-access = free | bibcode = 2015PLoSO..1017774D | url = }} T₁AM is not a ligand of the thyroid hormone receptors.{{cite journal | vauthors = Khan MZ, Nawaz W | title = The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system | journal = Biomed Pharmacother | volume = 83 | issue = | pages = 439–449 | date = October 2016 | pmid = 27424325 | doi = 10.1016/j.biopha.2016.07.002 | url = }} However, it is additionally a ligand of various monoamine and other receptors. For instance, it is a muscarinic acetylcholine receptor antagonist.{{cite journal | vauthors = Laurino A, Matucci R, Vistoli G, Raimondi L | title = 3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors | journal = Eur J Pharmacol | volume = 793 | issue = | pages = 35–42 | date = December 2016 | pmid = 27815171 | doi = 10.1016/j.ejphar.2016.10.027 | url = | hdl = 2158/1079396 | hdl-access = free }}

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.{{cite web |url=http://www.eurekalert.org/pub_releases/2004-05/ohs-ncm051404.php |title=New compound may act to keep thyroid activity in check |access-date=2008-05-30}} 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.{{cite journal |vauthors =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 |title=Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function |journal= The FASEB Journal|volume= 21|issue= 7|pages= 1597–608|year=2007 |pmid=17284482 |doi=10.1096/fj.06-7474com|doi-access=free |s2cid=14015560 }}

T₁AM has been found to produce TAAR1-dependent tyrosine hydroxylase (TH) phosphorylation in mouse dorsal striatum slices.{{cite journal | vauthors = Halff EF, Rutigliano G, Garcia-Hidalgo A, Howes OD | title = Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders | journal = Trends Neurosci | volume = 46 | issue = 1 | pages = 60–74 | date = January 2023 | pmid = 36369028 | doi = 10.1016/j.tins.2022.10.010 | url = | quote = 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]. | doi-access = free }}{{cite journal | vauthors = Zhang X, Mantas I, Alvarsson A, Yoshitake T, Shariatgorji M, Pereira M, Nilsson A, Kehr J, Andrén PE, Millan MJ, Chergui K, Svenningsson P | title = Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine | journal = Front Pharmacol | volume = 9 | issue = | pages = 166 | date = 2018 | pmid = 29545750 | pmc = 5837966 | doi = 10.3389/fphar.2018.00166 | doi-access = free | url = | quote = 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. }} 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.{{cite journal | vauthors = Piehl S, Hoefig CS, Scanlan TS, Köhrle J | title = Thyronamines--past, present, and future | journal = Endocr Rev | volume = 32 | issue = 1 | pages = 64–80 | date = February 2011 | pmid = 20880963 | doi = 10.1210/er.2009-0040 | url = | quote = 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). }}{{cite journal | vauthors = 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 | title = The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents | journal = Diabetes Obes Metab | volume = 11 | issue = 3 | pages = 251–260 | date = March 2009 | pmid = 18671794 | doi = 10.1111/j.1463-1326.2008.00935.x | url = }}