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

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, 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.

Tyramine and Octopamine Independently Inhibit Serotonin-Stimulated Aversive Behaviors inCaenorhabditis elegansthrough Two Novel Amine Receptors

“…Recently, a novel family of TAARs has been identified; however, in contrast to the classical BAs, much less is known about trace amine-mediated signaling. Both TAAR1 and TAAR2 bind TA and other ligands such as iodothyronamines, with high affinity and couple to G␣ s after heterologous expression (Borowsky et al, 2001;Bunzow et al, 2001;Hart et al, 2006). Based on studies in TAAR1 knock-out mice, amphetamines also appear to be high-potency agonists at TAAR1 receptors, and TAAR1 appears to modulate catecholaminergic function, suggesting that signaling through TAARs might provide useful targets for the treatment of a variety of behavioral disorders (Wolinsky et al, 2006).…”

ApoB-100-containing Lipoproteins Are Major Carriers of 3-Iodothyronamine in Circulation

“…T 1 AM and other thyronamines such as 3,3Ј,5,5Ј-tetraiodothyronamine (T 4 AM), 3,3Ј,5Ј-triiodothyronamine (rT 3 AM), 3,5,3Ј-triiodothyronamine (T 3 AM), 3,5-diiodothyronamine (3,5-T 2 AM), 3,3Ј-diiodothyronamine (3,3Ј-T 2 AM), and thyronamine (T 0 AM) were synthesized according to the literature (14). Anhydrous dimethylformamide (DMF) was obtained by passing through two columns of activated molecular sieves.…”

Trace amine-associated receptor 1—Family archetype or iconoclast?

“…Far from futile, the search for additional endogenous TAAR1 ligands has already led to the discovery of 3-iodothyronamine (T1AM) and its deiodinated relative thyronamine (T0AM), molecules that are closely related to thyroid hormone (Scanlan et al, 2004;Hart et al, 2006;Tan et al, 2007). Based on the structure activity profile compiled by Bunzow et al (2001) and the fact that the catecholamines and para-tyramine are all derivatives of the amino acid tyrosine (Y), Grandy and Scanlan conjectured that decarboxylated metabolites of thyroid hormone would be TAAR1 agonists.…”