WB4101-related compounds: new, subtype-selective alpha1-adrenoreceptor antagonists (or inverse agonists?)

J Med Chem. 2006 Nov 30;49(24):7140-9. doi: 10.1021/jm060358r.


Our previous structure-affinity relationship study had considered the enantiomers of the naphthodioxane, tetrahydronaphthodioxane, and 2-methoxy-1-naphthoxy analogues (compounds 1, 3, and 2, respectively) of 2-(2,6-dimethoxyphenoxyethylaminomethyl)-1,4-benzodioxane, the well-known alpha1-adrenoceptor (alpha1-AR) antagonist WB4101, showing that such modifications significantly modulate the affinity and selectivity profile for alpha1-AR subtypes and 5-HT1A receptor. Here, we extend investigations to antagonist activity enclosing new enantiomeric pairs, namely those of the methoxytetrahydronaphthoxy and methoxybiphenyloxy WB4101 analogues (4 and 5-7, respectively) and of a double-modified WB4101 derivative (8) resulting from hybridization between 2 and 3. We found that (S)-2 is a very potent (pA2 10.68) and moderately selective alpha1D-AR antagonist and the hybrid (S)-8 is a potent (pA2 7.98) and highly selective alpha1A-AR antagonist. Both of these compounds and (S)-WB4101 seem to act as inverse agonists in a vascular model. The results, which generally validate the logic we followed in designing these eight compounds, are acceptably rationalized by comparative SAR analysis of binding and functional affinities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists*
  • Animals
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dioxanes / chemical synthesis*
  • Dioxanes / chemistry
  • Dioxanes / pharmacology
  • Humans
  • In Vitro Techniques
  • Male
  • Methylamines / chemical synthesis*
  • Methylamines / chemistry
  • Methylamines / pharmacology
  • Organ Specificity
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis*
  • Tetrahydronaphthalenes / chemistry*
  • Tetrahydronaphthalenes / pharmacology


  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Biphenyl Compounds
  • Dioxanes
  • Methylamines
  • Tetrahydronaphthalenes
  • (2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane