Abstract

200 million people worldwide are living with a thyroid disorder related to a hormonal imbalance. Symptoms of this imbalance include deviations from normal heart rates and metabolic rates. A chemical messenger known as T3 has been shown to raise cardiac and metabolic rates, but this takes place on a timescale of hours. However, recent discoveries have revealed that a different thyroid hormone known as T1AM is capable of affecting some of these same physiological conditions in a matter of minutes. T1AM is a potent, selective agonist for the Trace Amine Associated Receptor (TAAR). Several studies have probed the structural basis of T1AM activation, but these studies have not yet provided a complete picture. Based on these findings, we have developed a new molecular scaffold that incorporates key structural features in a conformationally-restricted arrangement. For example, the incorporation of a six carbon ring in our target compounds will confine the location of the amine and even create multiple stereocenters. Furthermore, several chiral locations on this scaffold will have structural variability. To date, our research has focused on optimizing the reactions that produce 3-nitro-2H-chromenes, the chemical precursors to these target compounds. The successful production of a panel of these chromenes has set the stage for subsequent reactions that will allow us to generate many T1AM analogues. By understanding the regulation of TAAR we may gain a greater understanding of its role in biology and human physiology.