posted on 2007-06-14, 00:00authored byEdwin S. Tan, Motonori Miyakawa, James R. Bunzow, David K. Grandy, Thomas S. Scanlan
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.