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Background and Purpose 3-Iodothyroacetic acid (TA1) is an end product of thyroid hormone metabolism. So far, it is not known if TA1 is present in mouse brain and if it has any pharmacological effects. Experimental Approach TA1 levels in mouse brain were measured by HPLC coupled to mass spectrometry. After i.c.v. administration of exogenous TA1 (0.4, 1.32 and 4 μg·kg−1) to mice, memory acquisition-retention (passive avoidance paradigm with a light-dark box), pain threshold to thermal stimulus (51.5°C; hot plate test) and plasma glucose (glucorefractometer) were evaluated. Similar assays were performed in mice pretreated with s.c. injections of the histamine H1 receptor antagonist pyrilamine (10 mg·kg−1) or the H2 receptor antagonist zolantidine (5 mg·kg−1). TA1 (1.32 and 4 μg·kg−1) was also given i.c.v. to mice lacking histidine decarboxylase (HDC−/−) and the corresponding WT strain. Key Results TA1 was found in the brain of CD1 but not of HDC mice. Exogenous TA1 induced amnesia (at 0.4 μg·kg−1), stimulation of learning (1.32 and 4 μg·kg−1), hyperalgesia (0.4, 1.32 and 4 μg·kg−1) and hyperglycaemia (1.32 and 4 μg·kg−1). All these effects were modulated by pyrilamine and zolantidine. In HDC−/− mice, TA1 (1.32 and 4 μg·kg−1) did not increase plasma glucose or induce hyperalgesia. Conclusions and Implications Behavioural and metabolic effects of TA1 disclosed interactions between the thyroid and histaminergic systems.

Objective 3-Iodothyronamine (T1AM), an analog of thyroid hormone, is a recently discovered fast-acting endogenous metabolite. Single high-dose treatments of T1AM have produced rapid short-term effects, including a reduction of body temperature, bradycardia, and hyperglycemia in mice. Design and Methods The effect of daily low doses of T1AM (10 mg/kg) for 8 days on weight loss and metabolism in spontaneously overweight mice was monitored. The experiments were repeated twice (n = 4). Nuclear magnetic resonance (NMR) spectroscopy of plasma and real-time analysis of exhaled 13CO2 in breath by cavity ring down spectroscopy (CRDS) were used to detect T1AM-induced lipolysis. Results CRDS detected increased lipolysis in breath shortly after T1AM administration that was associated with a significant weight loss but independent of food consumption. NMR spectroscopy revealed alterations in key metabolites in serum: valine, glycine, and 3-hydroxybutyrate, suggesting that the subchronic effects of T1AM include both lipolysis and protein breakdown. After discontinuation of T1AM treatment, mice regained only 1.8% of the lost weight in the following 2 weeks, indicating lasting effects of T1AM on weight maintenance. Conclusions CRDS in combination with NMR and 13C-metabolic tracing constitute a powerful method of investigation in obesity studies for identifying in vivo biochemical pathway shifts and unanticipated debilitating side effects.

Background and Purpose 3-Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg−1, i.p.), an inhibitor of amine oxidative metabolism. Experimental Approach T1AM (0.13, 0.4, 1.32 and 4 μg·kg−1) or vehicle was injected i.c.v. into male mice, and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot plate and movements on the hole-board platform. Plasma glycaemia was measured using a glucorefractometer. Brain levels of triiodothyroxine (T3), thyroxine (T4) and T1AM were measured by HPLC coupled to tandem MS. ERK1/2 activation and c-fos expression in different brain regions were evaluated by Western blot analysis. Results T1AM improved learning capacity, decreased pain threshold to hot stimuli, enhanced curiosity and raised plasma glycaemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. T1AM effects on learning and pain were abolished or significantly affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at the rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behaviour. Conclusions And Implications T1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders.

BACKGROUND AND PURPOSE 3-iodothyronamine (T1AM) is a metabolite of thyroid hormone acting as a signalling molecule via non-genomic effectors and can reach intracellular targets. Because of the importance of mitochondrial F0F1-ATP synthase as a drug target, here we evaluated interactions of T1AM with this enzyme. EXPERIMENTAL APPROACH Kinetic analyses were performed on F0F1-ATP synthase in sub-mitochondrial particles and soluble F1-ATPase. Activity assays and immunodetection of the inhibitor protein IF1 were used and combined with molecular docking analyses. Effects of T1AM on H9c2 cardiomyocytes were measured by in situ respirometric analysis. KEY RESULTS T1AM was a non-competitive inhibitor of F0F1-ATP synthase whose binding was mutually exclusive with that of the inhibitors IF1 and aurovertin B. Both kinetic and docking analyses were consistent with two different binding sites for T1AM. At low nanomolar concentrations, T1AM bound to a high-affinity region most likely located within the IF1 binding site, causing IF1 release. At higher concentrations, T1AM bound to a low affinity-region probably located within the aurovertin binding cavity and inhibited enzyme activity. Low nanomolar concentrations of T1AM increased ADP-stimulated mitochondrial respiration in cardiomyocytes, indicating activation of F0F1-ATP synthase consistent with displacement of endogenous IF1,, reinforcing the in vitro results. CONCLUSIONS AND IMPLICATIONS Effects of T1AM on F0F1-ATP synthase were twofold: IF1 displacement and enzyme inhibition. By targeting F0F1-ATP synthase within mitochondria, T1AM might affect cell bioenergetics with a positive effect on mitochondrial energy production at low, endogenous, concentrations. T1AM putative binding locations overlapping with IF1 and aurovertin binding sites are described.

We developed a new efficient synthetic method for a 3-iodothyronamine (T1AM) that has advantages of less synthetic steps and much higher overall yield compared to those in the conventional method. Our animal study showed that T1AM synthesized by the method exerted a potent hypothermic effect in non-hibernator mice.

Objectives: T1AM subchronic low doses cause rapid lipolysis and weight loss with no change in food consumption. We investigated tissue specific effects of T1AM, a natural thyroid hormone analog, on metabolic pathways and associated transcriptional gene signaling and protein profiles. Methods: Three groups (n=5), randomly selected spontaneously obese female CD -1 mice were injected once daily for 7 days with saline, 10 mg/kg T1AM, or 25 mg/kg T1AM. Blood drawn on days -3, 4, and 7, was analyzed by 1H-NMR. Mice were sacrificed on day 7 and the organs collected for real-time PCR and protein profiles. Results: Multivariate analysis of the 1H-NMR data revealed increased 3-hydroxybutyrate and acetate and no differences in plasma glucose levels in T1AM-treated vs. control mice, . Mice treated with high dose T1AM show significant changes in tissue specific gene expression. The livers had increased expression of SIRT6 and GCK, and decreased expression of SIRT4, but in adipose tissue only SIRT6 increased. Protein e...

Recent studies have shown that, besides the well-recognized T-3 and T-4 hormones, there are other relevant thyroid hormones circulating in the human body. In particular, this is the case for 3-iodothyronamine (T(1)AM) and thyronamine (T(0)AM). One of the reasons for the lack of studies showing their precise importance is the absence of analytical methodologies available. Herein, for the first time, T(1)AM and T(0)AM are electrochemically characterized. T(0)AM was sensed by means of a glassy carbon electrode; furthermore, T(1)AM was sensed both with a graphitic surface (oxidatively) as well as with mercury (reductively). For both compounds, after oxidation, it was possible to observe the reversible redox reaction concerning the benzoquinone/hydroquinone couple, thus increasing the specificity of the electroanalysis. Therefore, this work provides the basis for an at-point-of-use' electrochemical strip test for T(1)AM and T(0)AM.

Compared to the conventional method the title synthesis has the advantage of less synthetic steps and higher overall yield.

The introduced synthesis has the advantages of reduced synthetic steps and significantly enhanced overall yield compared to the conventional method.

3‐Iodothyronamine (T1AM) is a novel metabolite of thyroid hormone. In HEK‐293 cells expressing an orphan G‐protein coupled receptor, the trace amine receptor, T1AM, potently increased cAMP accumulation. In mice, T1AM rapidly induced hypothermia and bradycardia within minutes of administration. These results suggest the existence of a new signaling pathway, the stimulation of which leads to rapid physiological and behavioral consequences. Isotope‐labeled T1AM derivatives would be useful to study the biology and pharmacology of T1AM. Herein we describe efficient syntheses of [125I]‐, [2H]‐, and [3H]‐T1AM.