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| 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 |
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| ECHA InfoCard | 100.211.501 |
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| Properties | |
| C14H14INO2 | |
| Molar mass | 355.17 g/mol |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
3-Iodothyronamine (T1AM) is anendogenousthyronamine. It is a high-affinityligand of thetrace amine-associated receptor 1 (TAAR1).[1][2] T1AM is the mostpotentendogenous TAAR1agonist yet discovered.[3] It is also anagonist of theTAAR2 andTAAR5 with similarpotency as for the TAAR1 (all in the case of the human proteins).[4][5] T1AM is not a ligand of thethyroid hormone receptors.[4] However, it is additionally a ligand of variousmonoamine and otherreceptors.[6] For instance, it is amuscarinic acetylcholine receptorantagonist.[7]
Activation of TAAR1 by T1AM results in the production of large amounts ofcyclic adenosine monophosphate (cAMP). This effect is coupled with decreasedbody temperature andcardiac output.[8] Wuet al. have pointed out that this relationship is not typical of theendocrine system, indicating that TAAR1 activity may not be coupled toG proteins in sometissues, or that T1AM may interact with other receptor subtypes.[3] T1AM may be part of asignaling pathway to modulatecardiac function, as the compound can induce negativeinotropic effects and decreasecardiac output.[9]
T1AM has been found to produce TAAR1-dependenttyrosine hydroxylase (TH)phosphorylation in mousedorsal striatumslices.[10][6] This phosphorylation would be expected to promote thefunctional activity of TH.[10][6] Accordingly, higher rates ofL-DOPA accumulation were observed after administration of T1AM in mice treated with aDOPA decarboxylase inhibitor.[10][6] The preceding effects were absent with TAAR1knockout mice or with the TAAR1antagonistEPPTB.[6] In addition, T1AM-mediated TH phosphorylation appeared to be mediated byCaMKII andprotein kinase A (PKA) signaling.[10][6] T1AM was also found to increase electrically evokeddopamine 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, thetrace aminesβ-phenethylamine andtyramine 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 onlocomotor activity in rodents at low doses but producedhypolocomotion at high doses.[11][12]
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.
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].
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).
