title: 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.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Wisconsin-Milwaukee, PO Box 413, Milwaukee, WI 53211, USA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Han
authors.forename: F
authors.initials: F
authors.lastname: Holger Försterling
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Damon
authors.initials: D
authors.lastname: Parrish
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.forename: Sundari
authors.initials: S
authors.lastname: Rallapalli
authors.forename: Terry
authors.initials: T
authors.lastname: Clayton
authors.forename: Yun
authors.initials: Y
authors.lastname: Teng
authors.forename: Samarpan
authors.initials: S
authors.lastname: Majumder
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sankar
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: Roman
authors.initials: R
authors.lastname: Furtmuller
authors.forename: James K
authors.initials: JK
authors.lastname: Rowlett
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weed
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: 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
chemical_list: D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010100:Oxygen
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