Comparative (Q)SAR analysis of benzodiazepine derivatives with different biological activity

Sobańska, Anna W.; Żydek, Grażyna; Włodno, Piotr; Brzezińska, Elżbieta

doi:10.1016/j.ejmech.2014.10.045

Cited by 10 publications

(10 citation statements)

References 41 publications

(44 reference statements)

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“…The correlations of the BBB permeability factors (for the compounds with the experimentally obtained BBB permeability) with the chromatographic parameters (R f and R f /PSA) have been investigated (Equations (1)-(3)). The strongest relationship (R = 0.67, n = 46) can be found for B2 (Equation (3)), which is in line with the observation that simpler models are usually better [48]. The experimental BBB permeability values for 46 compounds from the training set (1-46) were compared with the calculated B1 and B2 parameters and then with all the corresponding physicochemical parameters and chromatographic data.…”

Section: Stepwise Multiple Regression Analysissupporting

confidence: 63%

“…A number of computed or measured chromatographically (RP-18 TLC) BBB permeation descriptors have been presented in our previous papers [33,34,48]. The relationships between these descriptors and the observed (in vivo) BBB bioavailability were studied by MR and DF analysis for a group of compounds of diverse structures and successfully validated.…”

Section: Stepwise Multiple Regression Analysismentioning

confidence: 99%

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Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

2019

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The Blood-Brain Barrier (BBB) permeability is an important factor governing a drug’s ability to act upon the Central Nervous System. The measure of the BBB permeability used throughout this study is the log BB (the blood/brain partitioning coefficient) measured in vivo or calculated. Useful yet simple models of the BBB permeability were developed by Stepwise Multiple Regression Analysis based on the chromatographic parameters Rf and Rf/PSA obtained by RP-18 TLC with acetonitrile - pH 7.4 phosphate buffered saline 70:30 (v/v) as mobile phase, combined with descriptors - the number of H-bond donors (HD), the number of H-bond acceptors (HA), energy of the highest occupied molecular orbital – (eH), energy of the lowest unoccupied molecular orbital (eL). The ability of the solutes to cross the BBB has been studied qualitatively using Discriminant Function Analysis. Almost all compounds with the known BB vivo parameter were correctly classified as CNS+/-. The classification functions based on Rf/PSA have been verified using an external group. The results of the chromatographic analysis proposed in this study (RP-18 TLC) are a source of valuable information on the BBB permeability of compounds available even on a very small scale.

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Section: Stepwise Multiple Regression Analysissupporting

confidence: 63%

Section: Stepwise Multiple Regression Analysismentioning

confidence: 99%

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

2019

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“…Benzodiazepine interactions have been reported against cholecystokinin receptors, 29 α 2 -ARs, 30 HIV-1 reverse transcriptase, 30 κopioid receptors, 30 muscarinic receptors, 30 translocator protein, 31 Ca 2+ channels, 23 Ca 2+ /CaM-dependent protein kinases 32 , and PDE. 24,33 Using inhibitors of several of the other potential target proteins that could be responsible for CRE modulation we were able to conclude that inhibition of PDE, most likely PDE-4, by diazepam causes modulation of the CRE response ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Diazepam is not a direct allosteric modulator of α₁‐adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase‐4

Williams

Vaid

et al. 2018

Pharmacology Res & Perspec

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Abstractα1A‐ and α1B‐adrenoceptors (ARs) are G protein‐coupled receptors (GPCRs) that are activated by adrenaline and noradrenaline to modulate smooth muscle contraction in the periphery, and neuronal outputs in the central nervous system (CNS). α1A‐ and α1B‐AR are clinically targeted with antagonists for hypertension and benign prostatic hyperplasia and are emerging CNS targets for treating neurodegenerative diseases. The benzodiazepines midazolam, diazepam, and lorazepam are proposed to be positive allosteric modulators (PAMs) of α1‐ARs. Here, using thermostabilized, purified, α1A‐ and α1B‐ARs, we sought to identify the benzodiazepine binding site and modulatory mechanism to inform the design of selective PAMs. However, using a combination of biophysical approaches no evidence was found for direct binding of several benzodiazepines to purified, stabilized α1A‐ and α1B‐ARs. Similarly, in cell‐based assays expressing unmodified α1A‐ and α1B‐ARs, benzodiazepine treatment had no effect on fluorescent ligand binding, agonist‐stimulated Ca2+ release, or G protein activation. In contrast, several benzodiazepines positively modulated phenylephrine stimulation of a cAMP response element pathway by α1A‐ and α1B‐ARs; however, this was shown to be caused by off‐target inhibition of phosphodiesterases, known targets of diazepam. This study highlights how purified, stabilized GPCRs are useful for validating allosteric ligand binding and that care needs to be taken before assigning new targets to benzodiazepines.

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“…Benzodiazepines are one of the privileged class of nitrogen containing heteroaromatic compound in the area of pharmaceuticals and mainly acting on the central nervous system. Among the benzodiazepines, 1,3‐dihydro‐2 H ‐1,4‐benzodiazepin‐2‐one derivatives are the most abundant and have a well time‐honored position in antiepileptic therapy . In addition to their established anticonvulsant activity, 1,3‐Dihydro‐2 H ‐1,4‐benzodiazepin‐2‐one also demonstrates many other important biological activities such as anti‐anxiety, hypnotic, NNRTI of HIV‐1 reverse transcriptase, anti‐arrhythmic agents, antiproliferative, anti‐platelet anti‐ulcer, vasopressin antagonist activity, as well as anti‐inflammatory agents .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

Nilkanth¹,

Ghorai²,

Sathiyanarayanan

et al. 2020

Chemistry & Biodiversity

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A variety of 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethines and 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin‐induced seizure model. The prepared 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7‐{(E)‐[(4‐nitrophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐{(E)‐[(4‐bromo‐2,6‐difluorophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one and 7‐[(E)‐{[3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

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Comparative (Q)SAR analysis of benzodiazepine derivatives with different biological activity

Cited by 10 publications

References 41 publications

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

Diazepam is not a direct allosteric modulator of α₁‐adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase‐4

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

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Comparative (Q)SAR analysis of benzodiazepine derivatives with different biological activity

Cited by 10 publications

References 41 publications

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

Prediction of the Blood-Brain Barrier Permeability Using RP-18 Thin Layer Chromatography

Diazepam is not a direct allosteric modulator of α1‐adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase‐4

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

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Diazepam is not a direct allosteric modulator of α₁‐adrenoceptors, but modulates receptor signaling by inhibiting phosphodiesterase‐4