Synthesis, structure and affinity of novel 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones for CNS central and peripheral benzodiazepine receptors

被引：9

作者：

Andronati, Sergey ^{[1
]}

Semenishyna, Ekaterina ^{[1
]}

Pavlovsky, Victor ^{[1
]}

Simonov, Yuriy ^{[2
]}

Makan, Svetlana ^{[1
]}

Boyko, Irina ^{[1
]}

Burenkova, Natalya ^{[1
]}

Gdaniec, Maria ^{[3
]}

Cardinael, Pascal ^{[4
]}

Bouillon, Jean-Philippe ^{[4
]}

Mazepa, Alexander ^{[1
]}

机构：

[1] Natl Acad Sci Ukraine, AV Bogatsky Physicochem Inst, UA-65080 Odessa, Ukraine

[2] Moldavian Acad Sci, Inst Appl Phys, Kishinev, Moldova

[3] A Mitzkevitch Univ, Dept Chem, PL-60780 Poznan, Poland

[4] Univ Rouen, Sci & Methodes Separat EA 3233, IRCOF, F-76821 Mont St Aignan, France

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 45卷 / 04期

关键词：

3-alkoxy-1,2-dihydro-3H-1,4-bezodiazepin-2-ones; Enantiomer; Central benzodiazepine receptor; Peripheral benzodiazepine receptor; Affinity; X-ray analysis; GABA(A) RECEPTOR; PHARMACOLOGY; BINDING; ENANTIOMERS; LORAZEPAM; DIAZEPAM; OXAZEPAM; SUBTYPES; CRYSTAL; COMPLEX;

D O I：

10.1016/j.ejmech.2009.12.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 = 4930 nM). A high selectivity for CBR versus PBR (IC50 (PBR) > 10000 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. (C) 2009 Elsevier Masson SAS. All rights reserved.

引用

页码：1346 / 1351

页数：6

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