Update on 3-iodothyronamine and its neurological and metabolic actions

3-iodothyronamine (T1AM) is an endogenous amine, that has been detected in many rodent tissues, and in human blood. It has been hypothesized to derive from thyroid hormone metabolism, but this hypothesis still requires validation. T1AM is not a ligand for nuclear thyroid hormone receptors, but stimulates with nanomolar affinity trace amine-associated receptor 1 (TAAR1), a G protein-coupled membrane receptor. With a lower affinity it interacts with alpha2A adrenergic receptors. Additional targets are represented by apolipoprotein B100, mitochondrial ATP synthase, and membrane monoamine transporters, but the functional relevance of these interactions is still uncertain. Among the effects reported after administration of exogenous T1AM to experimental animals, metabolic and neurological responses deserve special attention, because they were obtained at low dosages, which increased endogenous tissue concentration by about one order of magnitude. Systemic T1AM administration favored fatty acid over glucose catabolism, increased ketogenesis and increased blood glucose. Similar responses were elicited by intracerebral infusion, which inhibited insulin secretion and stimulated glucagon secretion. However, T1AM administration increased ketogenesis and gluconeogenesis also in hepatic cell lines and in perfused liver preparations, providing evidence for a peripheral action, as well. In the central nervous system, T1AM behaved as a neuromodulator, affecting adrenergic and/or histaminergic neurons. Intracerebral T1AM administration favored learning and memory, modulated sleep and feeding, and decreased the pain threshold. In conclusion T1AM should be considered as a component of thyroid hormone signaling and might play a significant physiological and/or pathophysiological role. T1AM analogs have already been synthetized and their therapeutical potential is currently under investigation. 3-iodothyronamine (T1AM) is a biogenic amine whose structure is closely related to that of thyroid hormone (3,5,3′-triiodothyronine, or T3). The differences with T3 are the absence of the carboxylate group and the substitution of iodine with hydrogen in 5 and 3′ positions (Figure 1). In this paper we will review the evidence supporting the hypothesis that T1AM is a chemical messenger, namely that it is an endogenous substance able to interact with specific receptors producing significant functional effects. Special emphasis will be placed on neurological and metabolic effects, which are likely to have physiological and pathophysiological importance

Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

Background:Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.Methodology/Principal Findings:We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.Conclusions/Significance:Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. © 2013 Strandberg et al

Benzimidazole, benzoxazole and benzothiazole derivatives as 5HT(2B) receptor ligands. Synthesis and preliminary pharmacological evaluation

2-Phenethylbenzimidazole, 2-phenethylbenzoxazole and 2-phenethylbenzothiazole derivatives were synthesized to explore the structural features of the serotonin 5-HT2B receptor antagonists. Those molecules were designed to recognize the 5-HT2B receptor and to discriminate it from the 5-HT2A and 5-HT2C subtypes. All compounds were characterized by binding affinity determination for 5-HT2A and 5-HT2C subtypes and antagonistic activity for 5-HT2B receptor in rat stomach fundus. None of the new compounds showed affinity for 5-HT2A and 5-HT2C subtypes, but some of them displayed antagonistic activity in rat stomach fundus at micromolar concentrations

Tin(IV) and organotin(IV) complexes containing mono or bidentate N-donor ligands. V. Imidazole and imidazoline-2-thione derivatives: synthesis and spectroscopic charaeterization. Comparison with other imidazole tin(IV) complexes

The reactions of imidazole (L-1), benzimidazole (L-2), 2-phenylimidazole (L-3), 1-acetylimidazole (L-4), imidazoline-2(1,3H)-thione (L-5) and 1-methyl-imidazoline-2(3H)-thione (L-6) with RnSnCl4-n (R = Me-3 Bu-n or Ph; n =1, 2 or 3) were investigated. Twenty-seven navel adducts were obtained and characterized by analytical (elemental analysis conductivity and vaporimetric molecular weight measurements) and spectral (IR, far IR H-1 and Sn-119 NMR) data. The ligands L-1, L-2, L-3 and L-4 behave in the monodentate N-donor fashion, whereas L-5 and L-6 behave as monodentate S-donor molecules. Breaking of the N-CO bonds and protonation of imidazolate moiety occurred when the donor L-4 reacts with organotin accepters in not rigorously anhydrous conditions. The behavior of the adducts in acetone and chlorinated solvents is also discussed. Comparison was made with related organotin (IV) complexes of imidazoles

5HT2B receptor antagonists: a probe for spotting the pharmacophore

Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide range of pharmacological effects in the central and peripheral nervous systems. Advances in molecular biological techniques have led to the identification of seven classes of 5-HT receptor subtypes (5-HT1 – 5-HT7).1 The 5-HT2 family comprises the 5-HT2A, 5-HT2B and 5-HT2C subtypes, grouped in the same class on the basis of primary structure, signal transduction characteristics, and operational profile.2 Sequence analysis indicate approximately 80% amino acid homology in the seven transmembrane domains of the three receptors.3-5 Therefore, it is not surprising that many compounds once thought to be selective for the 5-HT2A receptor also bind with high affinity to the 5-HT2B and 5-HT2C subtypes. In the last few years some antagonists which begin to differentiate among the 5-HT2 subtypes – i. e. pyridylureas 1-2, indolylisothiazolylurea 3 and tetrahydro--carboline 4 (5-HT2B selective6,7) - , have been discovered. After a careful examination of these compounds can be hypothesized that the 3-pyridylurea, the 5-isothiazolylurea and the indole moieties share structural features which can affect the interaction with the 5-HT2B receptor. Thus, considering the structure of tetrahydro--carboline 4 and on the basis of previous considerations we have hypothesized that compounds originating from the general structure 5 may be useful tools to identify the structural requirements of 5-HT2B antagonists and to disclose the 5-HT2B receptor antagonist pharmacophore. All compounds were characterized by determination of binding affinities for 5-HT2A and 5-HT2C subtypes and antagonistic activity for 5-HT2B receptor in rat stomach fundus. The results will be discussed

Benzimidazole, benzoxazole and benzothiazole derivatives as 5HT 2B receptor ligands. Synthesis and preliminary pharmacological evaluation

none6Benzimidazole, bezoxazole and benzo thiazole derivatives were synthesized to explore the structural features of the serotonin 5HT2B antagonists. Binding affinity determination and pharmacological evaluation.noneGIORGIONI G; ACCORRONI B; DI STEFANO A; MARUCCI G; SINISCALCHI A.; CLAUDI FGiorgioni, G; Accorroni, B; DI STEFANO, A; Marucci, G; Siniscalchi, Anna; Claudi, F

Identit\ue0, profili, interazioni, scritture multimediali: modelli interpretativi e algoritmi per la costruzione di conoscenza on line e per l'analisi dell'interazione on line

La ricerca ha l\u2019obiettivo di individuare modelli interpretativi e algoritmi per l'analisi dell'interazione e della costruzione di conoscenza negli ambienti di apprendimento on line funzionali a supportare in itinere il lavoro dei docenti e dei tutor. In particolare si intende monitorare la partecipazione degli studenti alle attivit\ue0 formative e la costruzione di conoscenza in rete