Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences

J Med Chem. 2010 Oct 14;53(19):6986-95. doi: 10.1021/jm1006269.


We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology
  • Binding, Competitive
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Decerebrate State
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Humans
  • Hypothermia / chemically induced
  • Hypothermia / drug therapy
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Male
  • Mice
  • Molecular Conformation
  • Norepinephrine / metabolism
  • Polycyclic Compounds / chemical synthesis*
  • Polycyclic Compounds / chemistry
  • Polycyclic Compounds / pharmacology
  • Radioligand Assay
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship


  • 4-(1a,6-dihydro-1H-cyclopropa(a)inden-6a-yl)-1H-imidazole
  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Antihypertensive Agents
  • Imidazoles
  • Polycyclic Compounds
  • atipamezole
  • Norepinephrine