Thyronamines and Derivatives: Physiological Relevance, Pharmacological Actions, and Future Research Directions

Thyronamines (3-T(1)AM, T(0)AM) are endogenous compounds probably derived from L-thyroxine or its intermediate metabolites. Combined activities of intestinal deiodinases and ornithine decarboxylase generate 3-T(1)AM in vitro. Alternatively, 3-T(1)AM might be formed by the thyroid gland and secreted into the blood. 3-T(1)AM and T(0)AM concentrations have been determined by liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) in tissues, serum, and cell lines. However, large variations of 3-T(1)AM concentrations in human serum were reported by LC-MS/MS compared with a monoclonal antibody-based immunoassay. These differences might be caused by strong binding of the highly hydrophobic 3-T(1)AM to apolipoprotein B100. Pharmacological administration of 3-T(1)AM results in dose-dependent reversible effects on body temperature, cardiac function, energy metabolism, and neurological functions. The physiological relevance of these actions is unclear, but may occur at tissue concentrations close to the estimated endogenous concentrations of 3-T(1)AM or its metabolites T(0)AM or thyroacetic acid (TA(1)). A number of putative receptors, binding sites, and cellular target molecules mediating actions of the multi-target ligand 3-T(1)AM have been proposed. Among those are members of the trace amine associated receptor family, the adrenergic receptor ADR2a, and the thermosensitive transient receptor potential melastatin 8 channel. Preclinical studies employing various animal experimental models are in progress, and more stable receptor-selective agonistic and antagonistic analogues of 3-T(1)AM are now available for testing. The potent endogenous thyroid hormone-derived biogenic amine 3-T(1)AM exerts marked cryogenic, metabolic, cardiac and central actions and represents a valuable lead compound linking endocrine, metabolic, and neuroscience research to advance development of new drugs.