New pyrimido[5,4-b]indoles as Ligands for alpha(1)-adrenoceptor Subtypes

J Med Chem. 2003 Jul 3;46(14):2877-94. doi: 10.1021/jm0307741.

Abstract

A new series of compounds were designed as structural analogues of the alpha(1)-AR ligand RN5 (4), characterized by a tricyclic 5H-pyrimido[5,4-b]indole-(1H,3H)2,4-dione system connected through an alkyl chain to a phenylpiperazine (PP) moiety. These compounds were synthesized and tested in binding assays on human alpha(1A)-AR, alpha(1B)-AR, and alpha(1D)-AR subtypes expressed in HEK293 cells. Several structural modifications were performed on the PP moiety, the tricyclic system, and the connecting alkyl chain. Many of the new molecules showed a preferential affinity for the alpha(1D)-AR subtype. Some compounds, including 39 and 40, displayed substantial alpha(1D)-AR selectivity with respect to alpha(1A)-AR, alpha(1B)-AR, serotonergic 5-HT(1A), 5-HT(1B), 5-HT(2A), and dopaminergic D(1) and D(2) receptors. Two conformationally rigid analogues of 4, useful for studying the architecture of the receptor/ligand complex, were also prepared and tested. A subset of the new compounds was then used to evolve a preliminary pharmacophore model for alpha(1D)-AR antagonists, based on a more generalized model we had developed for alpha(1)-AR antagonists. This new model rationalized the relationships between structural properties and biological data of the pyrimido[5,4-b]indole compounds, as well as other compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Cell Line
  • Computer Simulation
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Ligands
  • Male
  • Models, Molecular
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Structure-Activity Relationship

Substances

  • ADRA1D protein, human
  • Adrenergic alpha-Antagonists
  • Indoles
  • Ligands
  • Pyrimidines
  • Receptors, Adrenergic, alpha-1