S. A. Andronati

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.

Analgesic Effects of 3-Substituted Derivatives of 1,4-Benzodiazepines and their Possible Mechanisms

In experiments on mice, we studied the analgesic activity of some 3-substituted derivatives of 1,4-benzodiazepines, including 3-propoxy-7-bromo-5-(2’-chloro)phenyl-1,2-dihydro-3Н-1,4-benzodiazepin-2-one (compound 6). This compound demonstrated clearly pronounced anti-inflammatory and antinociceptive properties in the acetic acid-induced writhing test (induction of visceral pain) in mice, test with carrageenan-induced paw edema in rats, and formalin test in mice. On multicellular preparations of circular smooth muscles from the fundal part of the rat stomach, we estimated the value of affinity of compound 6 (рKВ = 6.41). We hypothesize that the mechanism underlying inhibition of bradykinin (BK) receptors by compound 6 is mostly competitive. Therefore, compound 6 can be considered a promising basis for the development and synthesis of antagonists of BK receptors, which can be applied in clinical practice.

Quantitative structure-affinity relationship of 5-HT1A receptor ligands by the classification tree method

The influence of molecular structure of 346 ligands on their affinity for 5-HT1A receptors was investigated. It was shown that the effectiveness of the proposed novel approach for interpretation of decision tree models compared favourably with the PLS method. In the context of the proposed approach, molecular fragments and their values of the relative influence on the affinity for 5-HT1A receptors were defined.

Synthesis and DNA-Binding Properties of 9-Formylacridine and 9-Formylanthracene Aminoacetylhydrazones

The dependence of the affinity of compounds to DNA on the structure of their fragments intercalating into the double helix was studied in a series of aminoacetylhydrazones of 9-formylacridine and 9-formylanthracene. The synthesized compounds were characterized by the intercalating properties and the ability to inhibit the polymerase chain reaction (PCR). The affinity to DNA was found to be higher for acridine derivatives (log Ka = 7.37 – 8.04) than for anthracene derivatives (log Ka = 5.37 – 6.12). At the same time, both acridines and anthracenes showed insignificant ability to inhibit PCR. Thus, no correlation between the affinity to DNA and the ability to inhibit DNA replication was observed for the compounds studied.

N-[4-(arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximides and Their Epoxy Derivatives. Synthesis and affinity for 5-HT1a receptors

New ligands for 5-HT1A serotonin receptors, N-[4-(4-arylpiperazin-1-yl)butyl]bicyclo[2.2.1]hept-5-ene-endo-2,endo-3-dicarboximides and their epoxy derivatives, were synthesized, and their affinity for 5-HT1A receptors was estimated at 16.2 ± 2.0 to 0.60 ± 0.08 nM.

Interferon Induction Properties of Mono- and Bisacridines

Based on some special features of the antiviral and interferon induction activity of tilorone and taking into account the DNAintercalating ability of this compound, we suggested [1] that the mechanism of interferon induction is related to derepression of the interferon gene caused by the tilorone molecule intercalating predominantly in the region of regular codons. In addition, we formulated a hypothesis [2, 3] concerning the polymodal character of the antiviral activity of monoand bis-intercalators, including their potential ability of activating interferon synthesis.

1,5-Thione-thiol isomerization of 3-O-phosphorylated 1,4-benzodiazepine

Diphenylphosphinite, 1,4-benzodiazepine 3-O-derivative, was converted into the corresponding imides by the Staudinger reaction with azides of diphenylphosphinic, diphenylthiophosphinic, and diphenylphosphoric acids. The imide derived from azide of diphenylthiophosphinic acid undergoes the isomerization into the corresponding thiol when heated in the presence of catalytic amounts of a substituted 3-chloro-1,4-benzodiazepine.

Synthesis and anticonvulsant activity of 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones

A series of 3-alkoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones were synthesized and their anticonvulsant properties were studied. It was found that 7-bromo-5-phenyl-3-cyclopropylmethyloxy derivative VIII had the highest anticonvulsant action among the synthesized compounds, the value of which was comparable with that of the reference compound 7-bromo-3-hydroxy-5-(2′-chloro)phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (II). It was established that the 3-alkoxy-5-phenyl derivatives had higher anticonvulsant action than the 3-alkoxy-5-(2_-chloro)phenyl derivatives. The structures of compounds VIII and IX were determined by x-ray crystal and molecular structure analyses.

Effect of cinazepam administration on the ligand affinity of neuromediator system receptors in rat brain

The influence of single and long-term administration of cinazepam and zopiclon on the affinity of dopamine D1 and D2, serotonin 5-HT1A, cholecystokinin CCK2, and peripheral benzodiazepine receptors to the corresponding ligands in rat brain has been studied. The long-term administration of cinazepam changes the affinity of receptors to radiolabeled ligands to a much lower extent as compared to the administration of zopiclon.

Synthesis and structure of 3-arylidene and 3-hetarylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones and their affinity toward CNS benzodiazepine receptors

The condensation of 5-aryl-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-ones with aromatic aldehydes gives 5-aryl-3-arylidene-and 5-aryl-7-bromo-3-hetarylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones. X-ray diffraction structural analysis yielded the molecular and crystal structures of 7-bromo-3-(4′-methoxybenzylidene)-5-phenyl-1,2-dihydro-3H-1,4-diazepin-2-one and showed that this compound has cis configuration. Radioligand analysis was used to study the affinity of these products toward central nervous system and peripheral benzodiazepine receptors.