Guanidine-based α2-adrenoceptor ligands: Towards selective antagonist activity

Eur J Med Chem. 2014 Jul 23;82:242-54. doi: 10.1016/j.ejmech.2014.05.057. Epub 2014 May 27.


Depression has been linked to a selective increase in the high affinity conformation of the α2-adrenergic autoreceptors (α2-ARs) in the human brain as well as to an overexpression of α2-ARs in the hippocampus and cerebral cortex. Thus, the development of novel α2-AR antagonists represents an attractive source of new antidepressants. This paper describes the design, synthesis and pharmacological evaluation of 30 new guanidinium and 2-iminoimidazolidinium as potential α2-AR antagonists. In order to design this new series of α2-AR antagonists, a pharmacophore model was developed using the GALAHAD software. This study suggested that increased substitution in the space surrounding the cationic guanidine moiety might lead selectively to antagonist activity. Following the preparation of compounds incorporating this feature and competitive radioligand binding, [(35)S]GTPγS functional assays revealed that this structural modification affords exclusively α2-AR antagonists, in contrast with the analogous unsubstituted compounds in which a mixture of antagonist/agonist activities was previously observed.

Keywords: Alpha 2-adrenoceptor; Antagonists; Human prefrontal cortex tissue; Pharmacophore; [(35)S]GTPγS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Guanidine / chemical synthesis
  • Guanidine / chemistry
  • Guanidine / pharmacology*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • Receptors, Adrenergic, alpha-2
  • Guanidine