Trace Amine-Associated Receptor Agonists:  Synthesis and Evaluation of Thyronamines and Related Analogues

• Published in: Journal of medicinal chemistry Vol. 49; no. 3; pp. 1101 - 1112
• Main Authors: Hart, Matthew E, Suchland, Katherine L, Miyakawa, Motonori, Bunzow, James R, Grandy, David K, Scanlan, Thomas S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.02.2006; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Body Temperature - drug effects; Cell Line; Chemistry, Medicinal; Cyclic AMP - biosynthesis; Humans; Hypothermia - chemically induced; Life Sciences & Biomedicine; Medical sciences; Mice; Mice, Inbred C57BL; Miscellaneous; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - genetics; Science & Technology; Structure-Activity Relationship; Thyronines - chemical synthesis; Thyronines - chemistry; Thyronines - pharmacology; Transfection; CUPRIC ACETATE; HEART; THYROID-HORMONE; ACIDS; ARYLATION; PROTEIN-COUPLED RECEPTORS; IODINATION; VENTRICULAR MYOCYTES; Agonist; Rodentia; Aminoether; Trace amine associated receptor; In vitro; Iodine Organic compounds; Dose activity relation; In vivo; Signal transduction; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Benzenic compound; Chemical synthesis; Primary amine; Hypothermia; G protein; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0505718

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.