UCSF

Thyroid hormone is known to increase metabolism, core body temperature, and cardiac performance by regulating gene expression through the thyroid hormone nuclear receptors. These transcriptional effects have a slow onset and occur within hours to days. 3-Iodothyronamine (T1AM) is an endogenous, decarboxylated, and deiodinated metabolite of the thyroid hormone thyroxine that is found in the brain, heart, liver, and blood. When administered to mice intraperitoneally, T1AM rapidly induces hypothermia, anergia, and bradycardia; effects of which are opposite those observed with hyperthyroidism. In vitro, T1AM potently activates the orphan G-protein coupled receptor (GPCR) known as the trace amine-associated receptor 1 (TAAR1), inhibits neurotransmitter reuptake by the dopamine (DAT) and norepinephrine transporter (NET), and inhibits vesicular packaging by the vesicular monoamine transporter 2 (VMAT2). To understand the role of TAAR1 in mediating the effects of T1AM, we sought to develop small molecules that regulate the activity of TAAR1.

Structure-activity relationship studies on the ethylamine portion of T1AM showed that TAAR1 can tolerate prominent structural features found in existing GPCR agonists and antagonists. A closer investigation of the ligand-receptor interactions of existing catecholamine receptor drugs revealed a relationship between the functional properties of the ligand and how it interacts with the rotamer toggle switch residues of the receptor. Allowing the rotamer switch residues to toggle to their active conformation was associated with agonism while interfering with this conformational transition resulted in antagonism.

The rotamer toggle switch model of aminergic GPCR activation was a useful guideline in the design and synthesis of rat TAAR1 agonists and antagonists. It provided an insightful approach to understanding the molecular basis of rat TAAR1 activation by T1AM and related analogs, and guided the successful development of rat TAAR1 superagonists ET-36, ET-64, and ET-69 and lead antagonists ET-78, ET-92, and ET-93.