Novel Biphenyl Ureas as Regulators of the Trace Amine Associated Receptor

The thyroid hormone (TH) regulates many physiological functions in vertebrates including the cardiovascular system, metabolism, brain development, and growth. This can lead to serious physiological complications for patients suffering from a thyroid disorder. According to the American Thyroid Association as many as 20 million Americans suffer from thyroid diseases and 60% are unaware of their condition. Many people are misdiagnosed or symptoms go unrecognized because thyroid hormone biology is complicated and not completely understood. Consequently, the treatments for thyroid disorders are limited. The most common treatment is Synthroid, a synthetic thyroid hormone, which is taken orally and is one of the most commonly prescribed medications in the United States. The thyroid hormone is regulated by a cascade of hormone releases initiated by the hypothalamus, mediating the pituitary gland, and terminating in the stimulation of the thyroid gland. The activated thyroid gland releases TH into the blood stream. A negative feedback mechanism also exists, which terminates the signal from the hypothalamus if the concentration of TH gets too high. The hormones released from the thyroid gland are primarily T4, the inactive form of TH. T4 attaches to carrier proteins in the blood and it travels to its target cells. Upon reaching the target cell, T4 becomes activated through the action of a deiodinase to become T3. After activation, T3 activates its nuclear receptor leading to gene regulation and causes an increase in physiological functions. This is a slow process and can take hours or even days to see an effect. The biological processes that increase include metabolic rate, cardiac output, and body temperature among others. Recent research has shown that T1AM, a compound found in various tissues throughout the body, may play a role in thyroid hormone regulation. T1AM acts on the Trace Amine Associated Receptor (TAAR). TAAR activation leads to physiological effects in opposition to those induced by TH. This led to the proposal of a new homeostatic model for thyroid hormone regulation. It was traditionally thought that a person with hypothyroidism was suffering from too little T3, but the model suggests that they may have too much T1AM. And for a person with hyperthyroidism it is not that they have too much T3, but that they may have too little T1AM. The goal of this project is to develop novel T1AM derivatives to better understand the role of TAAR and T1AM in TH biology. Specifically, these compounds will incorporate an extra phenyl ring, and based on previous work, may be antagonists for TAAR. To this end, a synthesis of our novel phenyl substituted T1AM derivative was commenced with a commercially available compound. Thus far, the starting material has undergone two transformations: a boc protection and iodination. We have successfully separated the mono-boc protected amine and the mono-iodonated product from the di-products. The next step in the synthesis is the Suzuki coupling, which is currently being examined. Selective regulators for TAAR will be valuable biological tools that may lead to new treatments for thyroid disorders. *This scholar and faculty mentor have requested that only an abstract be published