Trace amine-associated receptor agonists

Synthesis and evaluation of thyronamines and related analogues

Matthew E. Hart, Katherine L. Suchland, Motonori Miyakawa, James R. Bunzow, David Grandy, Thomas (Tom) Scanlan

    Research output: Contribution to journalArticle

    98 Citations (Scopus)

    Abstract

    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 [Scanlan, T. S.; Suchland, K. L.; Hart, M. E.; Chiellini, G.; Huang, Y.; Kruzich, P. J.; Frascarelli, S.; Crossley, D. A.; Bunzow, J. R.; Ronca-Testoni, S.; Lin, E. T.; Hatton, D.; Zucchi, R.; Grandy, D. K. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med. 2004, 10 (6), 638-642]. 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, T1AM) except 91, which proved to be more efficacious. On the basis of this result, a dose-dependent profile for 91 was generated and an ED50 of 30 μmol/kg was calculated. Compound 91 proved to be more potent than T1AM 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.

    Original languageEnglish (US)
    Pages (from-to)1101-1112
    Number of pages12
    JournalJournal of Medicinal Chemistry
    Volume49
    Issue number3
    DOIs
    StatePublished - Feb 9 2006

    Fingerprint

    Hypothermia
    Amines
    Induced Hypothermia
    Thyroid Hormones
    Derivatives
    Chemical activation
    G-Protein-Coupled Receptors
    Pharmacology
    Metabolites
    thyronamine
    In Vitro Techniques
    3-iodothyronamine

    ASJC Scopus subject areas

    • Organic Chemistry

    Cite this

    Trace amine-associated receptor agonists : Synthesis and evaluation of thyronamines and related analogues. / Hart, Matthew E.; Suchland, Katherine L.; Miyakawa, Motonori; Bunzow, James R.; Grandy, David; Scanlan, Thomas (Tom).

    In: Journal of Medicinal Chemistry, Vol. 49, No. 3, 09.02.2006, p. 1101-1112.

    Research output: Contribution to journalArticle

    Hart, Matthew E. ; Suchland, Katherine L. ; Miyakawa, Motonori ; Bunzow, James R. ; Grandy, David ; Scanlan, Thomas (Tom). / Trace amine-associated receptor agonists : Synthesis and evaluation of thyronamines and related analogues. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 3. pp. 1101-1112.
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