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.

Androgens are well known for their many functions in promoting sexual differentiation and the induction of the male phenotype. In the male, the two endogenous androgens most active in promoting these effects are testosterone and nonaromatizable 5a-dihydrotestosterone (DHT). They also play important roles in the regulation of bone metabolism. The direct effects of androgen on bone cells is suggested by the presence of androgen receptors (AR) on several human and rat established osteoblast cell lines as well as normal human osteoblast cells (HOB).1) Androgens increase rates of cellular proliferation and differentiation of osteoblasts, increase TGF-b levels, increase production of matrix proteins and inhibit osteoclast function.2,3) A role of androgens in skeletal regulation is substantiated by numerous studies in human and rodents, demonstrating that chemical or surgical castration, as well as untreated hypogonadism in men and androgen deficiency in women with hypopituitarism, lead to accelerated bone loss.2,4-7) Importantly, the deleterious effects of these conditions on bone can be reversed by treatment with androgens.One apparently unique effect of androgens is to increase periosteal bone formation in cortical bone, while estrogens depress it.8) This reflects a major gender difference in bone size, which is one of important factors determining the bone strength. A number of studies provide the proof of principle that androgens are osteoanabolic in rodents, women and men. Nonaromatizable DHT increased cortical bone volume and periosteal bone formation rates when administrated to ovariectomized rats.9) The synthetic anabolic steroids, such as nandrolone decanoate or stanozolol, have been shown to increase bone mass in postmenopausal women, possibly via stimulation of bone formation.10,11) Beneficial anabolic effects of androgens on bone in postmenopausal osteoporosis are well-documented in recent studies using combined testosterone and estrogen administration.12,13) On the other hand, bone resorption inhibitors such as estrogens, bisphosphonates, selective estrogen receptor modulators (SERMs) and calcitonin, which are still first line of treatment/prevention of osteoporosis, are not sufficient to restore bone mass for patients who have already lost a significant amount of bone. In addition, bone turnover rate differs from site to site; higher in the cancellous bone of vertebrae than in the cortical bone of the long bones. Therefore, osteoanabolic agents, which increase cortical/periosteal bone formation and bone mass of long bones, would address unmet need in the treatment of osteoporosis especially for patients with high risk of fractures. The osteoanabolic agents also complement the bone resorption inhibitors that target the cancellous bones, leading to a biomechanically favorable bone structure. 14)Despite the beneficial effects of androgens in therapies for osteoporosis, hypogonadism and other androgen deficient diseases, clinical use of them has been limited because of the undesirable virilizing (acne, hirsu...

Thyroid hormone has long been known to have important transcriptional regulatory activities. Recently, however, the presence of endogenous derivatives of thyroid hormone, thyronamines, has been reported in various mammalian tissues. These derivatives have potent in vitro activity with a class of orphan G-protein-coupled receptors, the trace amine-associated receptors, and profound in vivo effects when administered to mice. We report here a novel neuromodulatory role for thyronamines. In synaptosomal preparations and heterologous expression systems, thyronamines act as specific dopamine and norepinephrine reuptake inhibitors. Thyronamines also inhibit the transport of monoamines into synaptic vesicles. These observations expand the nontranscriptional role of thyroid hormone derivatives and may help to explain the pharmacological effects of thyronamines in vivo.

3-iodothyronamine (1, T1AM) is a naturally occurring derivative of thyroid hormone that can potently activate the orphan G protein-coupled receptor (GPCR) known as the trace amine-associated receptor 1 (TAAR1). We have previously found that modifying the outer ring of the phenoxyphenethylamine core scaffold of 1 can improve potency and provide potent agonists. In this study, we explored the tolerance of rat and mouse TAAR1 (rTAAR1 and mTAAR1) for structural modifications in the ethylamine portion of 1. We found that incorporating unsaturated hydrocarbon substituents and polar, hydrogen-bond-accepting groups were beneficial for rTAAR1 and mTAAR1, respectively, providing compounds that were equipotent or more potent than 1. Additionally, we have discovered that a naphthyl group is an excellent isosteric replacement for the iodophenyl ring of 1.