High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones

Bioorg Med Chem. 2001 Feb;9(2):431-44. doi: 10.1016/s0968-0896(00)00262-5.

Abstract

A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cerebral Cortex / metabolism
  • GABA Agonists / chemical synthesis
  • GABA Agonists / chemistry
  • GABA Agonists / metabolism
  • GABA Antagonists / chemical synthesis
  • GABA Antagonists / chemistry
  • GABA Antagonists / metabolism
  • Inhibitory Concentration 50
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Male
  • Models, Molecular
  • Protein Binding
  • Pyrazoles / metabolism
  • Quantitative Structure-Activity Relationship*
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / metabolism*
  • Static Electricity

Substances

  • GABA Agonists
  • GABA Antagonists
  • Ligands
  • Pyrazoles
  • Quinolones
  • Receptors, GABA-A
  • 2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one