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 (TAAR ₁). 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 TAAR ₁ (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.