Determination of the stable conformation of GABA(A)-benzodiazepine receptor bivalent ligands by low temperature NMR and X-ray analysis.
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.
Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
Dongmei
D
Han
F Holger
FH
Försterling
Xiaoyan
X
Li
Jeffrey R
JR
Deschamps
Hui
H
Cao
James M
JM
Cook
D018360:Crystallography, X-Ray / Q000379:methods; D008024:Ligands; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D011485:Protein Binding / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D013696:Temperature
D008024:Ligands; D011963:Receptors, GABA-A