Esters of valerenic acid as potential prodrugs

Juliane Hintersteiner; Maximilian Haider; Denise Luger; Christoph Schwarzer; Gottfried Reznicek; Walter Jäger; Sophia Khom; Marko Mihovilovic; Steffen Hering

doi:10.1016/j.ejphar.2014.03.019

Esters of valerenic acid as potential prodrugs

Juliane Hintersteiner, Maximilian Haider, Denise Luger, Christoph Schwarzer, Gottfried Reznicek, Walter Jäger, Sophia Khom, Marko Mihovilovic, Steffen Hering

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Valerenic acid (VA) is a β _2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABA _A) 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 GABA _A 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 GABA _A (α ₁β ₃γ _2S) 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.

Original language	English
Pages (from-to)	123-131
Number of pages	9
Journal	European Journal of Pharmacology
Volume	735
Issue number	1
DOIs	https://doi.org/10.1016/j.ejphar.2014.03.019
Publication status	Published - 15 Jul 2014

Funding

The research was funded by the Austrian Science Fund (FWF) grants TRP 107-B11, P21241 and P22395. Juliane Hintersteiner and Denise Luger are fellows of the graduate school program MolTag (Austrian Science Fund FWF-W1232), Maximilian Haider is supported by the Initiativkolleg Functional Molecules IK 1041-N. The authors thank Hugo Kubinyi for valuable comments on the manuscript.

Austrian Fields of Science 2012

301206 Pharmacology

Keywords

GABA(A) receptors
Valerenic acid derivatives
Behavioral analysis
2-Microelectrode-voltage-clamp-technique
LC-MS/MS
BLOOD-BRAIN-BARRIER
GABA(A) RECEPTORS
NONSEDATING ANXIOLYTICS
XENOPUS OOCYTES
IN-VITRO
SUBUNIT
LORECLEZOLE
DERIVATIVES
MODULATION
ANTICONVULSANT

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10.1016/j.ejphar.2014.03.019

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title = "Esters of valerenic acid as potential prodrugs",

abstract = "Valerenic acid (VA) is a β 2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABA A) 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 GABA A 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 GABA A (α 1β 3γ 2S) 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.",

keywords = "GABA(A) receptors, Valerenic acid derivatives, Behavioral analysis, 2-Microelectrode-voltage-clamp-technique, LC-MS/MS, BLOOD-BRAIN-BARRIER, GABA(A) RECEPTORS, NONSEDATING ANXIOLYTICS, XENOPUS OOCYTES, IN-VITRO, SUBUNIT, LORECLEZOLE, DERIVATIVES, MODULATION, ANTICONVULSANT",

author = "Juliane Hintersteiner and Maximilian Haider and Denise Luger and Christoph Schwarzer and Gottfried Reznicek and Walter J{\"a}ger and Sophia Khom and Marko Mihovilovic and Steffen Hering",

note = "Funding Information: The research was funded by the Austrian Science Fund (FWF) grants TRP 107-B11 , P21241 and P22395 . Juliane Hintersteiner and Denise Luger are fellows of the graduate school program MolTag (Austrian Science Fund FWF-W1232), Maximilian Haider is supported by the Initiativkolleg Functional Molecules IK 1041-N . The authors thank Hugo Kubinyi for valuable comments on the manuscript.",

year = "2014",

month = jul,

day = "15",

doi = "10.1016/j.ejphar.2014.03.019",

language = "English",

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T1 - Esters of valerenic acid as potential prodrugs

AU - Hintersteiner, Juliane

AU - Haider, Maximilian

AU - Luger, Denise

AU - Schwarzer, Christoph

AU - Reznicek, Gottfried

AU - Jäger, Walter

AU - Khom, Sophia

AU - Mihovilovic, Marko

AU - Hering, Steffen

N1 - Funding Information: The research was funded by the Austrian Science Fund (FWF) grants TRP 107-B11 , P21241 and P22395 . Juliane Hintersteiner and Denise Luger are fellows of the graduate school program MolTag (Austrian Science Fund FWF-W1232), Maximilian Haider is supported by the Initiativkolleg Functional Molecules IK 1041-N . The authors thank Hugo Kubinyi for valuable comments on the manuscript.

PY - 2014/7/15

Y1 - 2014/7/15

N2 - Valerenic acid (VA) is a β 2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABA A) 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 GABA A 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 GABA A (α 1β 3γ 2S) 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.

AB - Valerenic acid (VA) is a β 2/3 subunit-specific modulator of γ-aminobutyric acid (GABA) type A (GABA A) 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 GABA A 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 GABA A (α 1β 3γ 2S) 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.

KW - GABA(A) receptors

KW - Valerenic acid derivatives

KW - Behavioral analysis

KW - 2-Microelectrode-voltage-clamp-technique

KW - LC-MS/MS

KW - BLOOD-BRAIN-BARRIER

KW - GABA(A) RECEPTORS

KW - NONSEDATING ANXIOLYTICS

KW - XENOPUS OOCYTES

KW - IN-VITRO

KW - SUBUNIT

KW - LORECLEZOLE

KW - DERIVATIVES

KW - MODULATION

KW - ANTICONVULSANT

UR - https://www.scopus.com/pages/publications/84899774796

U2 - 10.1016/j.ejphar.2014.03.019

DO - 10.1016/j.ejphar.2014.03.019

M3 - Article

SN - 0014-2999

VL - 735

SP - 123

EP - 131

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1

ER -

Esters of valerenic acid as potential prodrugs

Abstract

Funding

Austrian Fields of Science 2012

Keywords

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