Rational Design, Chemical Synthesis and Biological Evaluation of Novel Biguanides Exploring Species-Specificity Responsiveness of TAAR1 Agonists

Eur J Med Chem. 2018 Feb 25;146:171-184. doi: 10.1016/j.ejmech.2018.01.059. Epub 2018 Feb 4.


The design of novel chemical classes acting towards several G-protein-coupled receptors (GPCRs) represents a leading strategy in drug discovery, aimed at deriving effective and safe candidates for further assessment. During the last years, TAAR1 arose as a promising druggable target in medicinal chemistry, being of interest in the treatment of several pathologies, such as neuropsychiatric disorders, type 2 diabetes and obesity. Nevertheless, the limited number of known potent and selective ligands and the species-specificity responsiveness exhibited by those derivatives nowadays available make the discovery of novel compounds a challenging task. Herein, we discuss the development of two quantitative-structure activity relationship (QSAR) models around the agonism ability experienced by different chemo-types toward murine and human TAAR1 (m/hTAAR1) with the aim at deciphering some clues involved in their species-specificity responsiveness. Qualitatively, these information were evaluated guiding for the synthesis of novel ligands, which proved to feature selective agonism ability with respect to the mTAAR1 and hTAAR1 orthologues.

Keywords: Agonists; Biguanide; Docking; QSAR; TAAR1; Thyronamines.

MeSH terms

  • Biguanides / chemical synthesis
  • Biguanides / chemistry
  • Biguanides / pharmacology*
  • Bioluminescence Resonance Energy Transfer Techniques
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Quantitative Structure-Activity Relationship
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*


  • Biguanides
  • Receptors, G-Protein-Coupled
  • Trace amine-associated receptor 1