The analysis of the dose-effect pharmacological action for propoxazepam on the models of chemically and electrically induced seizures is carried out. The peculiarities of the compound influence on the different genesis seizures manifestations and their redistribution are determined. Pharmacological indices (therapeutic index, wideness, interval, and safety factor) have been calculated, which characterize the efficacy and safety of propoxazepam. The data presented suggest that the future use of propoxazepam as an antiepileptic agent is more secure in those pathologies that are more relevant to the GABA- and glycine-ergic mechanisms.

A series of 1-aryl-4-(phthalimidoalkyl) piperazines and 1-aryl-4-(naphthalimidoalkyl) piperazines were retrieved from a proprietary library based on their high structural similarity to haloperidol, an antipsychotic with antiparasitic activity, and assessed as potential antileishmanial scaffolds. Selected compounds were tested for antileishmanial activity against promastigotes of Leishmania major and Leishmania mexicana in dose-response assays. Two of the 1-aryl-4-(naphthalimidoalkyl) piperazines (compounds 10 and 11) were active against promastigotes of both Leishmania species without being toxic to human fibroblasts. Their activity was found to correlate with the length of their alkyl chains. Further analyses showed that compound 11 was also active against intracellular amastigotes of both Leishmania species. In promastigotes of both Leishmania species, compound 11 induced collapse of the mitochondrial electrochemical potential and increased the intracellular Ca2+ concentration. Therefore, it may serve as a promising lead compound for the development of novel antiparasitic drugs.

Aim.The purpose of this study was to characterize the Propoxazepam properties of bin ding to the human, dog and rat plasma proteins and to evaluate potential interspecies diffe rences in binding affinity.Methods.The stu dies on Plasma protein binding were conduc ted using the Rapid Equilibrium Dialysis system with subsequent LC MS/MS analysis.The albumin binding of the substances was cha racterized by the percentage of bound drug.Results.Propoxazepam was highly bound to the plasma proteins in rats, dogs and humans.The extent of Propoxazepam binding in human plasma was similar to that observed in rat plasma whereas it was slightly lower in dog plasma, following dialysis for 8 hours.Conclusions.No concentration dependent effects on plasma protein binding were observed in the species investigated for Propoxazepam.Overall mean free fractions of Propoxazepam were 1.60 %, 2.90 % and 1.96 % in rats, dogs and humans, respectively.The results obtained in this work gave insights on the role of HSA in distributing Propoxazepam to target tissues and in determining their pharmacological properties.The results are crucial for the development of Benzodizepines-based therapeutics drugs.

Cinazepam C19H14BrClN2O5, ("LevanaⓇ ІC") a partial GABAA receptor agonist, and its active metabolite 3-hydroxyphenazepam C15H10BrClN2O2 were comparatively assessed in vitro using nerve terminals isolated from rat cortex (synaptosomes). At the presynaptic site, cinazepam (100 and 200 µM) facilitated synaptosomal transporter-mediated [3H]GABA uptake by enhancing both the initial rate and accumulation, and decreased the ambient level and transporter-mediated release of [3H]GABA. Whereas, 3-hydroxyphenazepam decreased the uptake and did not change the ambient synaptosomal level and transporter-mediated release of [3H]GABA. To exclude GABA transporter influence, NO-711, the transporter blocker, was applied and it was found that exocytotic release of [3H]GABA decreased, whereas tonic release of [3H]GABA was not changed in the presence of both cinazepam or 3-hydroxyphenazepam after treatment of synaptosomes with NO-711. In fluorimetric studies using potential- and pH-sensitive dyes rhodamine 6G and acridine orange, respectively, it was found that cinazepam hyperpolarized the synaptosomal plasma membrane, and increased synaptic vesicle acidification, whereas, 3-hydroxyphenazepam demonstrated opposite effects on these parameters. Therefore, action of cinazepam and its active metabolite 3-hydroxyphenazepam on GABAergic neurotransmission was different. Therapeutic effects of cinazepam can be associated with its ability to hyperpolarize the plasma membrane, to increase synaptic vesicle acidification and capacity of its active metabolite 3-hydroxyphenazepam to inhibit GABA transporter functioning.

6-Amino-2-piperazinylquinazolin-4-one and 2-piperazinyl-4-phenylquinazoline derivatives were synthesized. The analgesic activity of the obtained series of derivatives was investigated and it was found that the synthesized compounds showed high analgesic activity. ED50 values range from 0.46 to 0.88 mg/kg.

Background. Propoxazepam, 7-bromo-5-(2-chlorophenyl)-3-propoxy-1H-benzo[e][1,4]diazepin-2(3H)-one, is a promising analgesic and anticonvulsant and is on preclinical trial. Objective. The aim of the research was to study the anti-inflammatory and analgesic action of Propoxazepam. Methods. The anti-inflammatory action was evaluated by carrageenan induced rat paw edema, formalin-induced paw licking response in mice and bradykinin-induced pain response in rat models. Results. It was established for the first time that the administration of Propoxazepam caused a significant anti-inflammatory activity when tested in different in vivo chemical experimental models of induced inflammation, i.e. carrageenan-, bradykinin- and formalin-induced inflammation tests. Conclusions. Propoxazepam significantly reduced acute and sub-acute inflammation and proved its efficacy and similar to anti-inflammatory action.

ХІМІЯВстановлення механізму тромбоутворення та його ролі в розвитку ряду небезпечних сер цево-судинних захворювань стимулювало пошук сполук, що перешкоджають агрегації тромбоцитів [1].Як ефективні лікарські засоби для профілактики і лікування тромбозів були запропоновані антагоністи фібриногенових рецепторів [2].Рецептор фібриногену (інтег рин  IIb  3 ) є важливою терапевтичною мішенню за перебігу тромботичних захворювань судин завдяки його ключовій ролі в процесі агрегації тромбоцитів.Формування тромбоцитарного агрегату відбувається в результаті утворення фібриногенових "містків" між  IIb  3рецепторами тромбоцитів.Фібриноген утворює комплекс з  IIb  3

It is known that 1,4-benzodiazepines have neurotropic properties. Relatively recently, we have shown that 2-arylidenesubstituted 1,4-benzodiazepines demonstrate pronounced analgesic properties. In this regard, the aim of this work is the synthesis of potential analgesics. In this article, the synthesis under conditions of interphase catalysis and the analgesic activity of 1-methoxycarbonylmethyl-7-bromo-5-phenyl-3-arylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones not previously described in the literature are described. It was shown that the application of the method using a saturated aqueous solution of potassium carbonate as the base and the use of tetrabutylammonium bromide (TBAB) as the phase transfer catalyst provides high yields of the expected products at an acceptable reaction rate. Our earlier attempt to use sodium methylate as the base in anhydrous aprotonic solvents leads to the formation of a large number of by-products, which subsequently made it difficult to process the reaction mixture and isolate the target compounds. The structure of the synthesized compounds was confirmed by mass spectrometry and 1H NMR spectroscopy. It was found that all compounds, tested for the presence of analgesic activity in in vivo experiments in mice, possess the analgesic activities which exceed the activity of the standard preparation «diclofenac – sodium». For the most active compounds, ED50 values were found for analgesic activity. These values were approximately 10 times higher than the value obtained for the standard preparation. It was found that in the synthesized series, the most active is compound 20 (ED50 = 0.60 ± 0,20 mg/kg), which contains a methoxy group in the arylidene fragment, a bromine atom is in the seventh position, and a phenyl substituent is in the fifth position.

Introduction. Propoxazepam (3-alcoxyderivative of 1.4-benzodiazepine), in the tail-flick test and picrotoxin-induced convulsions showed significant analgesic and antiepileptic activity. Flumazenil (GABA antagonist) reduced its analgesic action, although antiseizure activity was changed slightly. As specific propoxazepam actions are anticonvulsant (1 subtype GABAA-R) and analgesic (2 subtype GABAA-R in the spinal cord), it can be suggested that the substance has no abuse-related

3-Acyloxy-5-aryl-7-bromo-1,2-dihydro-3 H -1,4-benzodiazepin-2-ones ( 3 – 18 ) were synthesized and shown to possess (ED 50 = 0.05 – 5 mg/kg) hypnotic, sedative, anticonvulsant, and anxiolytic properties. The hypnotic activity of the tested compounds varied in the dose range 0.22 – 1.50 mg/kg i.p. in mice. The pharmacological properties of 3 – 14 were comparable to those of cinazepam (Levana ® IC) and its metabolite 3-hydroxyphenazepam. The CBDR affinity was shown to increase with acyl length in the series C2-C5 whereas it decreased significantly in the series C6-C8. The tested compounds were characterized by low toxicity with LD 50 > 650 mg/kg i.p. in mice.

Синтезированы производные 3-ацилокси-5-арил-7-бром-1,2-дигидро-3H-1,4-бенздиазепин-2-она (3 – 18). Показано, что изученные соединения (ЕД50 0,05 – 5 мг/кг) обладают снотворной, седативной, противосудорожной и анксиолитической активностью. Снотворная активность изученных соединений изменяется в интервале доз 0,22 – 1,50 мг/кг при внутрибрюшинном введении мышам. Соединения 3 – 14 по фармакологическим свойствам не уступают циназепаму (препарату Левана® ІС) и его метаболиту 3-гидроксифеназепаму. Показано, что в ряду 3-ацилпроизводных с длиной ацильного заместителя С2 – С5 наблюдается увеличение аффинитета к ЦБДР, а с длиной С6 – С8 — его значительное снижение. Исследуемые соединения являются малотоксичными, их LD50 > 650 мг/кг при внутрибрюшинном введении мышам.

The granulometric composition of new analgesic substance (7-bromo-5-(o-chlorophenyl)-3-propoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-one) was characterized by methods of crystals microscopy and lazer diffraction,. The single polymorphic phase demonstrated by differential scanning calorimetry, X-ray diffraction analysis, Raman and IR-spectroscopy. On the base of the anticonvulsive effect on mice in compare to coarse сcrystalline sample the conclusion about the higher pharmacological effect for the disperse sample had been demonstrated.

QSAR analysis of the structural infl uence of 3-substituted 1,2-dihydro-3Н-1,4-benzodiazepine derivatives on the thermodynamic characteristics (ΔН0, ΔS0 and ΔG0) of their complexation with compounds was the main problem of QSAR analysis in this study. For small sets a new approach was developed for constructing statistical models and estimating their predictive ability. The developed special procedure for the generation of ensembles of QSAR models made it possible to construct adequate «structure – thermodynamic parameters» models for an «extremely small» set (6 compounds). 2D-PLS QSAR models were developed using the structural descriptors calculated by Dragon program and the descriptors calculated by the method based on the simplex representation of the molecular structure. The consensus models with quite good statistical characteristics (R2 > 0.95 for work set, R2 test > 0.78 for test set) were obtained for thermodynamic charact eristics complexation of investigated compounds. The prognosis of the thermodynamic parameters of binding of the related compounds with R = H, iso-C4H9, sec.-C4H9 to the CBDR was carried out using the simplex descriptors and Dragon descriptors. The increa se in the corresponding alkyl substituent from ethyl to isomeric butyl does not signifi cantly affect the interaction of ligands with the CBDR. It is assumed that the amount of Hydrogen atoms bounding to the Carbon atom adjacent to the carbonyl group has a certain infl uence on the thermodynamic characteristics of ligands interaction with CBDR; this may be due to the hyperconjugation effect. Exner’s method has revealed that the mechanism of interaction of the methyl-substituted compound with the CBDR differs from the mechanism of interaction with the CBDR of other investigated compounds.

Effects of a propyloxy derivative of 1.4-benzodiazepine, propoxazepam, on GABA-benzodiazepine receptor complexes (GABA RCs) were examined in vitro and in vivo. The parameters of propoxazepam binding to synaptosomes from the rat brain were estimated in vitro. The Ki constant for inhibition of [3H] flumazenil binding by this agent was 3.5 ± 0.3 nM, on average. Considering the value of the GABA shift (1.9), propoxazepam can be considered as GABA-RC full agonist. On the model of picrotoxin-induced seizures in vivo, the propoxazepam average effective dose was estimated as 4.1 ± ± 0.21 mmol/kg. It was found that the parameters of myoclonic components (latent period of the onset of myoclonic seizures and their number), as well as death time of the tested animals, characterize adequately an anticonvulsant action of propoxazepam of picrotoxin-induced seizures in mice. Competitive interaction with picrotoxin is the possible mechanism of these effects at the level of GABAARCs. Significant deviations from a competitive model of monomolecular and cooperative binding of the agent at the receptor level have been found.

TSPO receptors are peripheral benzodiazepine receptors (PBDRs). Unlike central benzodiazepine receptors (CBDRs), PBDRs (TSPO receptors) are widely presented in organs and tissues of animals and humans; these receptors are involved significantly in the regulation of many physiological processes in the norm and pathologies. Elucidation of the molecular bases of interactions between the TSPO receptors and their ligands is an important task of modern pharmacochemistry. We studied the anxiolytic properties of some derivatives of 1-methoxycarbonylmethyl-3-arylamino-7-bromo-5-phenyl-1, 2-dihydro-3H-1,4-benzodiazepin-2-one (compounds 1-7), which demonstrate considerable affinity for TSPO and CBDRs. The anxiolytic activity was estimated in experiments on rats in the “Conflict situation” test, while the intensity of motor activity was estimated in the standard “Open field” test. All tested compounds demonstrated a rather high selectivity in binding with TSPO receptors; compounds 1–4 manifested significant anxiolytic properties. Compound 2 demonstrated the maximum anxiolytic activity; after binding with TSPO receptors, Ki(TSPO) = 19, while Ki(CBDRs) > 10000 nM. All studied compounds were characterized by low toxicity; their LD50 exceeded 500 mg/kg.

Damage to tissue, inflammation and disruption of normal functioning of organs are often accompanied by pain. In pain perceptions, the kinin-kallikrein system with bradykinin as mediator is very important. Regulatory activity of the kinin-kallikrein system permits the control of inflammation, pain, vascular tone and other functions. A new group of substances that may used for this purpose are 3-substituted 1,4-benzdiazepinones. We analyzed the effect of 3-aryl amino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction of the stomach in the presence of calcium channel blockers verapamil (1 μM) and gadolinium (300 μM). The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in the incubation solution were 10–6 M. Data processing on the dynamics of contraction was performed according to the method of T. Burdyha and S. Kosterin. Statistically significant changes were found for MX-1828. This compound reduced the maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of Gd3+ and verapamil by 19.3% and 32.0%, respectively. Also, MX-1828 demonstrated effects similar to those of the competitive inhibitor bradykinin B2-receptor – des-Arg9-bradykinin-acetate, which is possible evidence of its interaction with the receptor or signal transduction pathways. MX-1828 additionally reduced the maximum normalized rate of relaxation by 6.2% in the presence of Gd3+. This effect was demonstrated for MX-1906 in the presence of verapamil with additional reduction of the maximal normalized rate of relaxation, which was 26.4%. The results suggest the presence of inhibitory interaction between MX-1828 and kinin-kallikrein system receptors or signal transduction pathways. The effects which were found for MX-1906 require further studies to clarify the mechanisms of influence on bradykinin-induced smooth muscle contraction.

Among eight recently synthesized 3-phthalimidoacyloxy- and phthalimidoacyloxyethoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones, three compounds that enhanced the indices of cognitive functions in albino rats by 24-43%, as compared with those in control animals, were found. In the Morris water maze test, these agents used in doses of 10 mg/kg positively influenced the index of long-term memory in contrast to the hormone leptin (10 nM) that enhanced the index of short-term memory but did not influence long-term memory. Pyracetam enhanced the indices of both short-term memory and long-term memory, but only in a much greater dose (400 mg/kg). Injections of the above-mentioned three tested compounds into rats resulted in a decrease in the power of the delta EEG rhythm and also in rises in the powers of theta and (especially) beta oscillations. All eight tested compounds (in doses 10 mg/kg) demonstrated clearly pronounced antihypoxic effects under conditions of acute hypoxia in a closed space test in experiments on mice. Two compounds showed the maximum efficiency; those increased the survival time of mice by 76% and 50%, respectively, as compared with the control. Therefore, the eight tested compounds demonstrate, along with high antihypoxic efficiency, a specific aspect of pharmacological activity somewhat unusual for benzodiazepins; these compounds improve the long-term memory and learning capability and exert specific effects on the EEG characteristics. These compounds are characterized by low toxicity; their LD50 exceeds 550 mg/kg.

Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.

This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.