Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-adrenergic receptor blocking properties

Eur J Med Chem. 2011 Jul;46(7):3000-12. doi: 10.1016/j.ejmech.2011.04.032. Epub 2011 Apr 16.

Abstract

We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / chemical synthesis*
  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • Animals
  • Aorta / drug effects*
  • Benzodioxoles / chemical synthesis*
  • Benzodioxoles / pharmacology
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Hepatocytes / chemistry
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Phenylephrine / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology
  • Prazosin / metabolism
  • Prazosin / pharmacology
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Rabbits
  • Rats
  • Receptors, Adrenergic, alpha-1 / chemistry
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Sulfonamides / pharmacology
  • Tamsulosin
  • Tissue Culture Techniques
  • Tritium
  • Vasoconstriction / drug effects

Substances

  • 1-(2-(benzo(d)(1,3)dioxol-6-yl)ethyl)-4-(2-methoxyphenyl)piperazine
  • Adrenergic alpha-1 Receptor Antagonists
  • Benzodioxoles
  • Piperazines
  • Protein Isoforms
  • Receptors, Adrenergic, alpha-1
  • Sulfonamides
  • Tritium
  • Phenylephrine
  • Tamsulosin
  • Prazosin