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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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
Volume15
Issue number4
DOIs
StatePublished - Apr 21 2008

Fingerprint

Drug Design
G-Protein-Coupled Receptors
Switches
Hypothermia
Pharmaceutical Preparations
Biogenic Amines
Bradycardia
Molecular Structure
Thyroxine
Thyroid Hormones
Molecular structure
Conformations
Chemical activation
Pharmacology
Ligands
Derivatives
Trace amine-associated receptor 1

Keywords

  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Toward Deciphering the Code to Aminergic G Protein-Coupled Receptor Drug Design. / Tan, Edwin S.; Groban, Eli S.; Jacobson, Matthew P.; Scanlan, Thomas (Tom).

In: Chemistry and Biology, Vol. 15, No. 4, 21.04.2008, p. 343-353.

Research output: Contribution to journalArticle

Tan, Edwin S. ; Groban, Eli S. ; Jacobson, Matthew P. ; Scanlan, Thomas (Tom). / Toward Deciphering the Code to Aminergic G Protein-Coupled Receptor Drug Design. In: Chemistry and Biology. 2008 ; Vol. 15, No. 4. pp. 343-353.
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