Determination of the stable conformation of GABA(A)-benzodiazepine receptor bivalent ligands by low temperature NMR and X-ray analysis

Bioorg Med Chem Lett. 2004 Mar 22;14(6):1465-9. doi: 10.1016/j.bmcl.2004.01.018.

Abstract

The stable conformations of GABA(A)-benzodiazepine receptor bivalent ligands 2 and 3 were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity as illustrated for alpha5 subtype selective ligand 2 (15 nM). Bivalent ligand 3 with the 5 atom linker folded back upon itself both in solution and in the solid state, moreover, it did not bind to Bz receptors.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Crystallography, X-Ray / methods
  • Ligands
  • Molecular Conformation
  • Nuclear Magnetic Resonance, Biomolecular / methods*
  • Protein Binding / physiology
  • Receptors, GABA-A / chemistry*
  • Receptors, GABA-A / metabolism*
  • Temperature

Substances

  • Ligands
  • Receptors, GABA-A