title: Esters of valerenic acid as potential prodrugs.
abstract: Valerenic acid (VA) is a β2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABAA) receptors inducing anxiolysis. Here we analyze if VA-esters can serve as prodrugs and if different ester structures have different in vitro/in vivo effects. Modulation of GABAA receptors expressed in Xenopus oocytes was studied with 2-microelectrode-voltage-clamp. Anxiolytic effects of the VA-esters were studied on male C57BL/6N mice by means of the elevated plus maze-test; anticonvulsant properties were deduced from changes in seizure threshold upon pentylenetetrazole infusion. VA was detected in plasma confirming hydrolysis of the esters and release of VA in vivo. Esterification significantly reduced the positive allosteric modulation of GABAA (α1β3γ2S) receptors in vitro. in vivo, the studied VA-ester derivatives induced similar or even stronger anxiolytic and anticonvulsant action than VA. While methylation and propylation of VA resulted in faster onset of anxiolysis, the action of VA-ethylester was longer lasting, but occurred with a significant delay. The later finding is in line with the longer lasting anticonvulsant effects of this compound. The estimated VA plasma concentrations provided first insight into the release kinetics from different VA-esters. This might be an important step for its future clinical application as a potential non-sedative anxiolytic and anticonvulsant.
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: juliane.hintersteiner@univie.ac.at.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hintersteiner
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria. Electronic address: maximilian.haider@univie.ac.at.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Haider
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: denise.luger@univie.ac.at.
authors.forename: Denise
authors.initials: D
authors.lastname: Luger
authors.affiliation: Department of Pharmacology, Innsbruck Medical University, Peter-Mayr-Straße 1, 1a A-6020 Innsbruck, Austria. Electronic address: schwarzer.christoph@i-med.ac.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: gottfried.reznicek@univie.ac.at.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Reznicek
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: walter.jaeger@univie.ac.at.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: sophia.khom@univie.ac.at.
authors.forename: Sophia
authors.initials: S
authors.lastname: Khom
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria. Electronic address: marko.mihovilovic@tuwien.ac.at.
authors.forename: Marko D
authors.initials: MD
authors.lastname: Mihovilovic
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address: steffen.hering@univie.ac.at.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D000927:Anticonvulsants / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D004952:Esters; D018682:GABA Agents / Q000627:therapeutic use*; D007192:Indenes / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D009865:Oocytes; D010433:Pentylenetetrazole; D011355:Prodrugs / Q000627:therapeutic use*; D011963:Receptors, GABA-A / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014981:Xenopus
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D004952:Esters; D018682:GABA Agents; D007192:Indenes; D011355:Prodrugs; D011963:Receptors, GABA-A; D012717:Sesquiterpenes; C037133:valerenic acid; D010433:Pentylenetetrazole
keywords: 2-Microelectrode-voltage-clamp-technique; Behavioral analysis; GABA(A) receptors; LC–MS/MS; Valerenic acid derivatives