Tuning the predictive capacity of the PAMPA-BBB model

Müller, Judit; Esső, Katalin; Dargó, Gergő; Könczöl, Árpád; Balogh, György Tibor

doi:10.1016/j.ejps.2015.08.019

Cited by 34 publications

(30 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each compound was measured in triplicate. The effective permeability (P e ) was calculated using the following equation 41 :

P_{e} = \frac{2.303}{A \cdot false(t - τ_{s s} false)} \cdot \frac{V_{A} \cdot V_{D}}{false(V_{A} + V_{D} false)} \cdot l g [1 - (1 \frac{V_{A} + V_{D}}{(1 - R) \cdot V_{D}}) \cdot (1 \frac{C_{A} (t)}{C_{D} (0)})]

, where P e is the effective permeability (cm/s), V A and V D are the volume of the acceptor and donor well (0.25 cm 3 ), respectively, C A (t) is the concentration of the acceptor well at time t, C D (0), C D (t) is the concentration of the donor well at t 0 and t, respectively, A is the filter well area (0.21 cm 2 ). t is the incubation time (s).…”

Section: Methodsmentioning

confidence: 99%

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

Wang

et al. 2017

J. Med. Chem.

View full text Add to dashboard Cite

Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (Ki = 26 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively.

show abstract

“…Each compound was measured in triplicate. The effective permeability (P e ) was calculated using the following equation 41 :

P_{e} = \frac{2.303}{A \cdot false(t - τ_{s s} false)} \cdot \frac{V_{A} \cdot V_{D}}{false(V_{A} + V_{D} false)} \cdot l g [1 - (1 \frac{V_{A} + V_{D}}{(1 - R) \cdot V_{D}}) \cdot (1 \frac{C_{A} (t)}{C_{D} (0)})]

Section: Methodsmentioning

confidence: 99%

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

Wang

et al. 2017

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…However, modern methods do exist, including computational and non-cell-based in vitro approaches. Among them Parallel Artificial Membrane Permeability Assays (PAMPAs) and quantitative structure-activity relationship (QSAR) analysis both provide fast analysis of BBB permeation, which is of particular importance in the early stages of drug discovery processes [19][20][21]. In the area of the CNS, there are widely used QSAR predictive models [22] based on various combinations of physicochemical parameters.…”

Section: Introductionmentioning

confidence: 99%

In Silico Studies on Triterpenoid Saponins Permeation through the Blood–Brain Barrier Combined with Postmortem Research on the Brain Tissues of Mice Affected by Astragaloside IV Administration

Stępnik

Kukuła-Koch

2020

IJMS

View full text Add to dashboard Cite

As the number of central nervous system (CNS) drug candidates is constantly growing, there is a strong need for precise a priori prediction of whether an administered compound is able to cross the blood–brain barrier (BBB). The aim of this study was to evaluate the ability to cross the BBB of triterpenoid saponins occurring in Astragalus mongholicus roots. The research was carried out using in silico methods combined with postmortem studies on the brain tissues of mice treated with isolated astragaloside IV (AIV). Firstly, to estimate the ability to cross the BBB by the tested saponins, new quantitative structure–activity relationship (QSAR) models were established. The reliability and predictability of the model based on the values of the blood–brain barrier penetration descriptor (logBB), the difference between the n-octanol/water and cyclohexane/water logP (ΔlogP), the logarithm of n-octanol/water partition coefficient (logPow), and the excess molar refraction (E) were both confirmed using the applicability domain (AD). The critical leverage value h* was found to be 0.128. The relationships between the standardized residuals and the leverages were investigated here. The application of an in vitro acetylcholinesterase-inhibition test showed that AIV can be recognized as the strongest inhibitor among the tested compounds. Therefore, it was isolated for the postmortem studies on brain tissues and blood using semi-preparative HPLC with the mobile phase composed of water, methanol, and ethyl acetate (1.7:2.1:16.2 v/v/v). The results of the postmortem studies on the brain tissues show a regular dependence of the final concentration of AIV in the analyzed brain samples of animals treated with 12.5 and 25 mg/kg b.w. of AIV (0.00012299 and 0.0002306 mg, respectively, per one brain). Moreover, the AIV logBB value was experimentally determined and found to be equal to 0.49 ± 0.03.

show abstract

“…The latter achieved the best outcomes probably owing to its cerebral origin, thus with a higher likelihood of mimicking the lipid composition of brain endothelial cells [108,109]. The PAMPA assay with the porcine polar brain lipid (PBL) showed the best discriminating attributes between CNS+ and CNS-samples [109] and strongly correlated to in situ brain perfusion [111].…”

Section: Physical Configurationmentioning

confidence: 95%

“…Consequently, a proper choice of the solvent must be made [115]. Most researchers focus on hydrocarbon solvents, such as n-dodecane (the most broadly used up to date) [109], hexane [108,116], n-hexadecane or other viscous alkanes [113].…”

Section: Organic Solventmentioning

confidence: 99%

“…To draw some conclusions from PAMPA results, a classification range must be first established for high (CNS+) and low (CNS-) BBB permeation into the CNS, based on the PAMPA permeability coefficients obtained for standards with known in vivo performance. This discrimination range is then used to divide samples with unknown performance into CNS+ or CNS-categories according to their experimental permeability coefficients [108]. Traditionally, the establishment of this discrimination range stems from an in vitro-in vivo comparison between PAMPA permeability coefficients and in vivo brain:blood ratio -a parameter that quantifies the extent of permeation- [109].…”

Section: Parallel Artificial Membrane Permeability Assay (Pampa)mentioning

confidence: 99%

See 1 more Smart Citation

In vitro screening of nanomedicines through the blood brain barrier: A critical review

2016

View full text Add to dashboard Cite

Tuning the predictive capacity of the PAMPA-BBB model

Cited by 34 publications

References 35 publications

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker

In Silico Studies on Triterpenoid Saponins Permeation through the Blood–Brain Barrier Combined with Postmortem Research on the Brain Tissues of Mice Affected by Astragaloside IV Administration

In vitro screening of nanomedicines through the blood brain barrier: A critical review

Contact Info

Product

Resources

About