Pharmacodynamics of Interaction between Propoxazepam and a GABA-Benzodiazepine Receptor-Ionofor Complex

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

Pharmacodynamics of Interaction between Propoxazepam and a GABA-Benzodiazepine Receptor-Ionofor Complex

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

QSAR ANALYSIS OF COMPLEXATION OF ETHERS OF 7-BROM-3-HYDROXY-5-(2'-CHLORO) PHENYL-1,2-DIHYDRO-3H-1,4-BENZODIAZEPIN-2-ONES WITH CENTRAL BENZODIAZEPINE RECEPTORS CNS

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

QSAR АНАЛІЗ КОМПЛЕКСОУТВОРЕННЯ ЕСТЕРІВ 7-БРОМ-3-ГІДРОКСИ-5-(2’-ХЛОР)ФЕНІЛ-1,2-ДИГІДРО-3Н-1,4-БЕНЗДІАЗЕПІН-2-ОНІВ З ЦЕНТРАЛЬНИМИ БЕНЗДІАЗЕПІНОВИМИ РЕЦЕПТОРАМИ ЦНС

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.Проведено QSAR аналіз впливу структури похідних 3-заміщених 1,4-бенздіазепінів на термодинамічні характеристики (ΔН0, ΔS0 и ΔG0) їх комплексоутворення з центральними бенздіазепіновими рецепторами (ЦБДР) ЦНС. Основною проблемою аналізу виявилась незначна кількість досліджуваних сполук, у зв’язку з чим було розроблено новий підхід для малих вибірок щодо побудови статистичних моделей та оцінки їхньої прогнозувальної здатності. Використовуючи спеціальну процедуру для формування навчальних та тестових вибірок, структурні дескриптори, розраховані за допомогою програми Dragon, і дескриптори, розраховані в рамках методу, що базується на симплексному представленні молекулярної структури, було побудовано адекватні 2D-PLS моделі «структура - термодинамічні параметри» для «надзвичайно малого» набору досліджуваних речовин (6 сполук). Отримані моделі мають задовільні статистичні характеристики: R2 > 0.95 для навчальної вибірки, R2 test > 0.78 для тестової вибірки. З метою більш детального аналізу впливу замісника на термодинамічні характеристики похідних 3-заміщених 1,4-бенздіазепінів було спрогнозовано значення ΔН0, ΔS0 і ΔG0 комплексеутворення з ЦБДР для сполук з R = H, i-C4H9, s-C4H9.Встановлено, що збільшення довжини і розгалуженості відповідного алкільного заступника від етилу до ізомерних бутилів не суттєво впливає на взаємодію лігандів з ЦБДР. Зроблено припущення, що певний вплив на термодинамічні характеристики взаємодії лігандів з ЦБДР має кількість атомів Гідрогену, які зв’язані з атомом Карбону алкілу, що знаходиться поряд з карбонільною групою, що може бути пов’язано з ефектом гіперкон’югації. Метод Екснера дозволив виявити, що механізм взаємодії метил-заміщеної сполуки з ЦБДР відрізняється від механізму взаємодії з ЦБДР інших досліджуваних сполук