edoc

GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding.

Zabela, Volha and Hettich, Timm and Schlotterbeck, Götz and Wimmer, Laurin and Mihovilovic, Marko D. and Guillet, Fabrice and Bouaita, Belkacem and Shevchenko, Bénédicte and Hamburger, Matthias and Oufir, Mouhssin. (2018) GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding. Journal of Chromatography B, 1072. pp. 379-389.

Full text not available from this repository.

Official URL: https://edoc.unibas.ch/63326/

Downloads: Statistics Overview

Abstract

In 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.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Biologie (Hamburger)
UniBasel Contributors:Hamburger, Matthias and Zabela, Volha and Oufir, Mouhssin
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1570-0232
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:23 Mar 2019 08:02
Deposited On:23 Mar 2019 08:02

Repository Staff Only: item control page