In vitro blood-brain barrier permeability predictions of piperine analogues with GABAA receptor modulating properties

Eigenmann, Daniela E. and Dürig, Carmen and Jähne, Evelyn A. and Smieško, Martin and Culot, Maxime and Gosselet, Fabien and Cecchelli, Romeo and Cederberg Helms, Hans Christian and Brodin, Birger and Wimmer, Laurin and Mihovilovic, Marko D. and Hamburger, Matthias and Oufir, Mouhssin. (2016) In vitro blood-brain barrier permeability predictions of piperine analogues with GABAA receptor modulating properties. European Journal of Pharmaceutics and Biopharmaceutics, 103. pp. 118-126.

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Official URL: http://edoc.unibas.ch/43379/

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The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood–brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00–500 ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molecular Modeling (Vedani)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Hamburger, Matthias and Eigenmann, Daniela and Jähne, Evelyn and Oufir, Mouhssin and Smiesko, Martin
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:28 Nov 2017 10:05
Deposited On:13 Dec 2016 09:06

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