Design, Synthesis, and Evaluation of Thyronamine Analogues as Novel Potent Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists

J Med Chem. 2015 Jun 25;58(12):5096-107. doi: 10.1021/acs.jmedchem.5b00526. Epub 2015 Jun 5.


Trace amine associated receptor 1 (TAAR1) is a G protein coupled receptor (GPCR) expressed in brain and periphery activated by a wide spectrum of agonists that include, but are not limited to, trace amines (TAs), amphetamine-like psychostimulants, and endogenous thyronamines such as thyronamine (T0AM) and 3-iodothyronamine (T1AM). Such polypharmacology has made it challenging to understand the role and the biology of TAAR1. In an effort to understand the molecular basis of TAAR1 activation, we rationally designed and synthesized a small family of thyronamine derivatives. Among them, compounds 2 and 3 appeared to be a good mimic of the parent endogenous thyronamine, T0AM and T1AM, respectively, both in vitro and in vivo. Thus, these compounds offer suitable tools for studying the physiological roles of mouse TAAR1 and could represent the starting point for the development of more potent and selective TAAR1 ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blood Glucose / metabolism
  • Drug Design
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Thyronines / chemistry
  • Thyronines / pharmacology


  • Blood Glucose
  • Ligands
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • Thyronines
  • thyronamine
  • Trace amine-associated receptor 1