Exploring the structure-activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1.

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.