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

Abstract

Thyronamines (3-TAM, TAM) are endogenous compounds probably derived from L-thyroxine or its intermediate metabolites. Combined activities of intestinal deiodinases and ornithine decarboxylase generate 3-TAM in vitro. Alternatively, 3-TAM might be formed by the thyroid gland and secreted into the blood. 3-TAM and TAM 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-TAM 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-TAM to apolipoprotein B100. Pharmacological administration of 3-TAM 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-TAM or its metabolites TAM or thyroacetic acid (TA). A number of putative receptors, binding sites, and cellular target molecules mediating actions of the multi-target ligand 3-TAM have been proposed. Among those are members of the trace amine associated receptor family, the adrenergic receptor ADRα2a, 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-TAM are now available for testing. The potent endogenous thyroid hormone-derived biogenic amine 3-TAM 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.

Trace Amines and Their Receptors

“…Although it is often reported as a derivative/metabolite of thyroid hormones (Hoefig et al, 2016), whether 3IT is indeed derived from either 3,39,5-triiodothyronine or thyroxine after decarboxylation and deiodination is a matter of some conjecture (Ackermans et al, 2010;Hoefig et al, 2011Hoefig et al, , 2015. The available evidence indicates that 3IT is not formed by the action of AADC Hoefig et al, 2012) but may be formed by ornithine decarboxylase (EC 4.1.1.17) (Hoefig et al, 2015).…”

“…A variety of physiologic effects of 3IT have been reported and a number of reviews of such effects have previously been published to which the reader is referred for further details (Ianculescu and Scanlan, 2010;Zucchi et al, 2010Zucchi et al, , 2014Piehl et al, 2011;Hoefig et al, 2016). Here, we will provide a brief overview of such effects with the following caveat: the promiscuous nature of 3IT makes it highly unlikely that all, or even most, of the physiologic effects described are mediated via one or more TAARs.…”

“…Where there is unequivocal evidence of TAAR-mediated 3IT responses, these are discussed in the subsequent sections focused on those individual receptor subtypes. Furthermore, it was recently suggested that at least some of the effects previously ascribed to 3IT may in fact be a function of one or more of its metabolites (Hoefig et al, 2016;Laurino and Raimondi, 2017), adding a further level of complexity to the elucidation of the physiologic relevance and pharmacological effects of 3IT.…”

Triiodothyroacetic acid in health and disease

“…Other modifications of iodothyronines include decarboxylation of the alanine side chain, resulting in iodothyronamines (Scanlan et al 2004, Hoefig et al 2015, and subsequent oxidative deamination resulting in the formation of iodothyroacetic acid derivatives (Wood et al 2009). Recently, potential biological actions have been ascribed to 3-iodothyronamine (3-T 1 AM) and thyronamine (T 0 AM) (reviewed in Hoefig et al 2016). The biological actions of 3,3′,5-triiodothyroacetic acid (Triac; TA 3 ) and 3,3′,5,5′-tetraiodothyroacetic acid (Tetrac, TA 4 ) have been more extensively described.…”

Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?

“…“ Such potent actions of 3-T1AM, its metabolites, and synthetic congeners are of eminent interest in emergency and critical care medicine, surgery, tissue transplantation, metabolic and eye clinics, as well as space science. Application of an endogenous biogenic cryogen derived from a hormone provides a rather safe and valuable “lead compound” to be tested and developed by the pharmaceutical industry for various medical applications …” (16). “ From the current body of literature, potential therapeutic applications with T1AM are quite apparent, ranging from sleep/torpidity induction, conferring protection against ischemic injury, and anti-obesogenic by inducing increased metabolic reliance on lipid oxidation ” (17).…”