A study of the structure-activity relationship of GABA(A)-benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis.
The stable conformations of GABA(A)-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 alpha5 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.
Han
Dongmei
D
Department of Chemistry, University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, WI 53211, USA.
Holger Försterling
F
F
Li
Xiaoyan
X
Deschamps
Jeffrey R
JR
Parrish
Damon
D
Cao
Hui
H
Rallapalli
Sundari
S
Clayton
Terry
T
Teng
Yun
Y
Majumder
Samarpan
S
Sankar
Subramaniam
S
Roth
Bryan L
BL
Sieghart
Werner
W
Furtmuller
Roman
R
Rowlett
James K
JK
Weed
Michael R
MR
Cook
James M
JM
D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003080:Cold Temperature; D018360:Crystallography, X-Ray; D019281:Dimerization; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010100:Oxygen
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