title: Synthesis, structure and affinity of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones for CNS central and peripheral benzodiazepine receptors.
abstract: A series of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones (7-15) was synthesized and their in vitro affinity for both the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PBR) of rat brain was studied. Racemic mixture of 7-bromo-3-(2-methoxy)ethoxy-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (13) was separated into enantiomers 14, 15 by chiral HPLC. Absolute configuration of R-enantiomer 15 was determined by the method of X-ray diffraction analysis. The affinity of S-enantiomer 14 for CBR ( IC50)=245 nM) is 20-fold higher than the affinity of R-enantiomer 15 (IC50)=4,930 nM). A high selectivity for CBR versus PBR (IC50) (PBR)>10,000 nM) was shown by all reported compounds. Compound 12 was revealed as a potent (IC50)=9 nM) and selective CBR ligand among the synthesized 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones.
authors.affiliation: A.V. Bogatsky Physico-Chemical, Institute of the National Academy of Sciences of Ukraine, 86 Lustdorfskaya doroga, 65080 Odessa, Ukraine.
authors.forename: Sergey
authors.initials: S
authors.lastname: Andronati
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Semenishyna
authors.forename: Victor
authors.initials: V
authors.lastname: Pavlovsky
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Simonov
authors.forename: Svetlana
authors.initials: S
authors.lastname: Makan
authors.forename: Irina
authors.initials: I
authors.lastname: Boyko
authors.forename: Natalya
authors.initials: N
authors.lastname: Burenkova
authors.forename: Maria
authors.initials: M
authors.lastname: Gdaniec
authors.forename: Pascal
authors.initials: P
authors.lastname: Cardinael
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Bouillon
authors.forename: Alexander
authors.initials: A
authors.lastname: Mazepa
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
chemical_list: D011963:Receptors, GABA-A; D001569:Benzodiazepines