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dc.contributor.authorZabela, Volha
dc.contributor.authorHettich, Timm
dc.contributor.authorSchlotterbeck, Götz
dc.contributor.authorWimmer, Laurin
dc.contributor.authorMihovilovic D., Marko
dc.contributor.authorGuillet, Fabrice
dc.contributor.authorBelkacem, Bouaita
dc.contributor.authorShevchenko, Bénédicte
dc.contributor.authorHamburger, Matthias
dc.contributor.authorOufir, Mouhssin
dc.date.accessioned2018-12-13T09:56:38Z
dc.date.available2018-12-13T09:56:38Z
dc.date.issued2017-12
dc.identifier.doi10.1016/j.jchromb.2017.11.036
dc.identifier.urihttp://hdl.handle.net/11654/26969
dc.description.abstractIn a screening of natural products for allosteric modulators of GABAA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABAA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds.
dc.description.urihttps://www.ncbi.nlm.nih.gov/pubmed/29227934
dc.language.isoen
dc.relation.ispartofJournal of chromatography. B, Analytical technologies in the biomedical and life sciences
dc.accessRightsAnonymous
dc.subjectGABA(A)
dc.subjectIn vitro metabolism
dc.subjectPiperine analogs
dc.subjectSilensomes
dc.subjectUHPLC-Q-TOF-MS
dc.titleGABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding
dc.type01 - Zeitschriftenartikel, Journalartikel oder Magazin
dc.volume2018
dc.issue1072
dc.audienceScience
fhnw.publicationStatePublished
fhnw.ReviewTypeAnonymous ex ante peer review of a complete publication
fhnw.InventedHereYes
fhnw.PublishedSwitzerlandNo
fhnw.pagination379-389
fhnw.IsStudentsWorkno
fhnw.publicationOnlineJa


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