Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties

J Med Chem. 2001 Mar 1;44(5):787-805. doi: 10.1021/jm001040g.


Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-naphthalenyl)methyl]-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.

MeSH terms

  • Adrenergic Uptake Inhibitors / chemical synthesis*
  • Adrenergic Uptake Inhibitors / chemistry
  • Adrenergic Uptake Inhibitors / metabolism
  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / metabolism
  • Animals
  • Antidepressive Agents / chemical synthesis*
  • Antidepressive Agents / chemistry
  • Antidepressive Agents / metabolism
  • Binding Sites
  • Binding, Competitive
  • CHO Cells
  • Cerebral Cortex / metabolism
  • Cricetinae
  • Frontal Lobe / metabolism
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • In Vitro Techniques
  • Indans / chemical synthesis*
  • Indans / chemistry
  • Indans / metabolism
  • Ligands
  • Norepinephrine / antagonists & inhibitors
  • Rats
  • Receptors, Adrenergic, alpha-2 / drug effects*
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Serotonin Uptake Inhibitors / chemical synthesis*
  • Serotonin Uptake Inhibitors / chemistry
  • Serotonin Uptake Inhibitors / metabolism
  • Structure-Activity Relationship


  • 4(5)-((5-fluoroindan-2-yl)methyl)-4,5-dihydroimidazole
  • Adrenergic Uptake Inhibitors
  • Adrenergic alpha-Antagonists
  • Antidepressive Agents
  • Imidazoles
  • Indans
  • Ligands
  • Receptors, Adrenergic, alpha-2
  • Serotonin Uptake Inhibitors
  • Norepinephrine