A study of the structure-activity relationship of GABAA-benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis

Dongmei Han, F. Holger Försterling, Xiaoyan Li, Jeffrey R. Deschamps, Damon Parrish, Hui Cao, Sundari Rallapalli, Terry Clayton, Yun Teng, Samarpan Majumder, Subramaniam Sankar, Bryan L. Roth, Werner Sieghart, Roman Furtmuller, James K. Rowlett, Michael R. Weed, James M. Cook

Research output: Contribution to journalArticlepeer-review

Abstract

The stable conformations of GABAA-benzodiazepine receptor bivalent ligands were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The stable conformations in solution correlated well with those in the solid state. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity and was illustrated for α5 subtype selective ligands. Bivalent ligands with an oxygen-containing linker folded back upon themselves both in solution and the solid state. Dimers which are folded do not bind to Bz receptors.

Original languageEnglish (US)
Pages (from-to)8853-8862
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number19
DOIs
StatePublished - Oct 1 2008

Keywords

  • Benzodiazepines
  • Conformation
  • GABA
  • NMR

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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