Synthesis, structure and affinity of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones for CNS central and peripheral benzodiazepine receptors.
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.
Andronati
Sergey
S
A.V. Bogatsky Physico-Chemical, Institute of the National Academy of Sciences of Ukraine, 86 Lustdorfskaya doroga, 65080 Odessa, Ukraine.
Semenishyna
Ekaterina
E
Pavlovsky
Victor
V
Simonov
Yuriy
Y
Makan
Svetlana
S
Boyko
Irina
I
Burenkova
Natalya
N
Gdaniec
Maria
M
Cardinael
Pascal
P
Bouillon
Jean-Philippe
JP
Mazepa
Alexander
A
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
D011963:Receptors, GABA-A; D001569:Benzodiazepines