Synthesis, Testing and Structure-Activity Studies on a Library of 5-HT4 Ligands Academic Article uri icon

abstract

  • Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT₄ receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 µM. The most potent of these (20) had a pKi of 8.54 demonstrating very good affinity. These indole analogues were combined with 55 ligands that were previously produced in our laboratory to explore the structure-activity relationships of these 5-HT₄ ligands. A CoMFA (Comparative Molecular Field Analysis) analysis was used to extend an earlier simple pharmacophore to suggest two new molecular features beyond the primary amino binding site. The pharmacophore confirmed that a newly described tetrahydroquinoline analogue was able to match the basic requirements of the model and the pharmacology of this molecule is provided in more detail.

authors

  • Irving, Helen
  • Hanna-Elias, Amir
  • T. Manallack, David
  • Levit, Alla
  • Nguyen, William
  • Ayad, Fadi
  • Perera, Glen
  • Shapiro, Marina
  • R. Irving, Helen
  • M. Coupar, Ian
  • N. Iskander, Magdy

publication date

  • November 1, 2010