title: In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.
abstract: 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 5.00-500ng/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.
authors.affiliation: Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Daniela Elisabeth
authors.initials: DE
authors.lastname: Eigenmann
authors.affiliation: Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dürig
authors.affiliation: Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Evelyn Andrea
authors.initials: EA
authors.lastname: Jähne
authors.affiliation: Molecular Modeling, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Smieško
authors.affiliation: Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300 Lens Cedex, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Culot
authors.affiliation: Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300 Lens Cedex, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Gosselet
authors.affiliation: Univ. Artois, EA 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300 Lens Cedex, France.
authors.forename: Romeo
authors.initials: R
authors.lastname: Cecchelli
authors.affiliation: Drug Transporters in ADME, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Hans Christian Cederberg
authors.initials: HCC
authors.lastname: Helms
authors.affiliation: Drug Transporters in ADME, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Birger
authors.initials: B
authors.lastname: Brodin
authors.affiliation: Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9, A-1060 Vienna, Austria.
authors.forename: Laurin
authors.initials: L
authors.lastname: Wimmer
authors.affiliation: Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9, A-1060 Vienna, Austria.
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
authors.affiliation: Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
authors.affiliation: Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Electronic address: mouhssin.oufir@unibas.ch.
authors.forename: Mouhssin
authors.initials: M
authors.lastname: Oufir
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D006801:Humans; D066298:In Vitro Techniques; D010539:Permeability; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011963:Receptors, GABA-A; C008922:piperine
keywords: GABA(A) receptor; Human stem cells; Immortalized cell line; In silico prediction; In vitro blood–brain barrier (BBB) model; Permeability coefficient; Piperine; Primary cells; UHPLC-MS/MS