Toward Deciphering the Code to Aminergic G Protein-Coupled Receptor Drug Design

Edwin S. Tan, Eli S. Groban, Matthew P. Jacobson, Thomas S. Scanlan

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


The trace amine-associated receptor 1 (TAAR1) is a biogenic amine G protein-coupled receptor (GPCR) that is potently activated by 3-iodothyronamine (1, T1AM) in vitro. Compound 1 is an endogenous derivative of the thyroid hormone thyroxine which rapidly induces hypothermia, anergia, and bradycardia when administered to mice. To explore the role of TAAR1 in mediating the effects of 1, we rationally designed and synthesized rat TAAR1 superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation. The functional activity of a ligand is proposed to be correlated to its probable interactions with the rotamer switch residues; agonists allow the rotamer switch residues to toggle to their active conformation, whereas antagonists interfere with this conformational transition. These agonist and antagonist design principles provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalChemistry and Biology
Issue number4
StatePublished - Apr 21 2008



ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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