High affinity ligands and potent antagonists for the α1D-adrenergic receptor. Novel 3,8-disubstituted [1]benzothieno[3,2-d]pyrimidine derivatives

Eur J Med Chem. 2014 Aug 18:83:419-32. doi: 10.1016/j.ejmech.2014.06.057. Epub 2014 Jun 26.

Abstract

A new series of high affinity ligands and antagonists for the α1D-adrenergic receptor (AR) has been discovered. New molecules present a [1]benzothieno[3,2-d]pyrimidin-2,4(1H,3H)-dione or a [1]benzothieno[3,2-d]pyrimidin-4(3H)-one scaffold and bear a 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl moiety in the 3-position and various amide substituents in the 8-position. In binding assays at the three human cloned α1A-, α1B-, and α1D-AR subtypes, they showed high affinity values, particularly for the α1D-AR subtype. Compound 22 (RX18), N(1)-methyl-N(5)-[3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-2,4-dioxo-1,2,3,4-tetrahydro[1]benzothieno[3,2-d]pyrimidin-8-yl]-N(1)-(phenylmethyl)pentanediamide, was the most interesting in the series displaying very high affinity (pKi = 10.25) and potent antagonism (pKb = 9.15) when tested in a functional assay at the α1D-AR.

Keywords: Antagonist; Ligand; [1]Benzothieno[3,2-d]pyrimidine; α(1D)-Adrenergic receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / chemistry*
  • Adrenergic alpha-1 Receptor Antagonists / metabolism
  • Adrenergic alpha-1 Receptor Antagonists / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Muscle Contraction / drug effects
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Structure-Activity Relationship

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Ligands
  • Pyrimidines
  • Receptors, Adrenergic, alpha-1