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Scanlan
Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues.Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS. J Med Chem. 2006 Feb 9;49(3):1101-12. [abstract only]
"We have previously
shown that several thyronamines, decarboxylated and deiodinated
metabolites of the thyroid hormone, potently activate an orphan G
protein-coupled receptor in vitro (TAAR1) and induced hypothermia
in vivo on a rapid time scale. Herein, we report the
synthesis of these thyronamines. Additionally, a large number of
thyroamine derivatives were synthesized in an effort to
understand the molecular basis of TAAR1 activation and
hypothermia induction. Several derivatives were found to potently
activate both rTAAR1 and mTAAR1 in vitro (compounds 77, 85, 91,
and 92). When administered to mice at a 50 mg/kg dose, these
derivatives all induced significant hypothermia within 60 min and
exhibited a hypothermic induction profile analogous to
3-iodothyronamine (1, T(1)AM) except 91, which proved to be more
efficacious. On the basis of this result, a dose-dependent
profile for 91 was generated and an ED(50) of 30 mumol/kg was
calculated. Compound 91 proved to be more potent than T(1)AM for
TAAR1 activation and exhibits increased potency and efficacy for
hypothermia induction. These data further strengthen the
pharmacological correlation linking TAAR1 activation by
thyronamines and hypothermia induction in mice."
3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone.Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK. Nat Med. 2004 Jun;10(6):638-42. Epub 2004 May 16. [abstract only]
"Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH."
New compound may act to keep thyroid activity in check: OHSU study finds T1 amine rapidly causes hypothermia, blood pressure drop, slow pulseMay 2004 [news report of Scanlan, 2004]
"Although the compound, 3-iodothyronamine – T1 amine, for short – is a derivative of thyroxine, an essential thyroid hormone that influences development, body temperature, metabolic rate and cardiac performance, it has the opposite effect of thyroxine, according to a study by scientists at Oregon Health & Science University, the University of California, San Francisco (UCSF) and Universita di Pisa, Italy. The new findings suggest that T1 amine affects several organ systems. Consequently, if its molecular and cellular actions can be precisely described, physicians will be in a better position to treat a variety of cardiovascular and endocrine diseases, as well as mental health disorders, said David Grandy, Ph.D., associate professor of physiology and pharmacology, and cell and developmental biology in the OHSU School of Medicine. "Here we thought we knew thyroid hormone so well, only to find out there's this whole new aspect of it," said Grandy, co-author of a study published in today's online edition of the journal Nature Medicine. T1 amine's "normal function in the body may be to counteract, or keep in check, thyroid hormone's actions."
A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor.Chiellini G, Apriletti JW, Yoshihara HA, Baxter JD, Ribeiro RC, Scanlan TS. Chem Biol. 1998 Jun;5(6):299-306. [abstract only]
"BACKGROUND: Thyroid hormones regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor (TR), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. There are two different genes that encode two different TRs, TR alpha and TR beta, and these two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities. RESULTS: We have designed and synthesized a thyroid hormone analog that has high affinity for the TRs and is selective in both binding and activation functions for TR beta over TR alpha. The compound, GC-1, was initially designed to solve synthetic problems that limit thyroid hormone analog preparation, and contains several structural changes with respect to the natural hormone 3,5,3'-triiodo-L-thyronine (T3). These changes include replacement of the three iodines with methyl and isopropyl groups, replacement of the biaryl ether linkage with a methylene linkage, and replacement of the amino-acid sidechain with an oxyacetic-acid sidechain. CONCLUSIONS: The results of this study show that GC-1 is a member of a new class of thyromimetic compounds that are more synthetically accessible than traditional thyromimetics and have potentially useful receptor binding and activation properties. The TR beta selectivity of GC-1 is particularly interesting and suggests that GC-1 might be a useful in vivo probe for studying the physiological roles of the different thyroid hormone receptor isoforms."
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