Valerenic acid derivatives as novel subunit-selective GABA(A) receptor ligands - in vitro and in vivo characterization

Sophia Khom, Barbara Strommer, Jürgen Ramharter, Thomas Schwarz, Christoph Schwarzer, Thomas Erker, Gerhard Ecker, Johann Mulzer, Steffen Hering (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed


Background and Purpose Subunit-specific modulators of ?-aminobutyric acid (GABA) type A (GABAA) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a ?2/3 subunit-specific modulator of GABAA receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABAA receptor modulators and to gain insight into the structure-activity relation of this molecule. Experimental Approach The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABA A receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (IGABA) through GABAA receptors (EC50) and efficacies (maximal stimulation of IGABA) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. Key Results Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater IGABA enhancement than VA) and highest potency (EC50 = 13.7 ± 2.3 ?M) on ?1?3 receptors. Higher efficacy and potency of VA-A were also observed on ?1?2? 2s and ?3?3?2s receptors. Anxiolytic effects were most pronounced for VA-A. Conclusions and Implications Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting ?3 subunit containing GABAA receptors for development of anxiolytics.
Seiten (von - bis)65-78
FachzeitschriftBritish Journal of Pharmacology
PublikationsstatusVeröffentlicht - 2010

ÖFOS 2012

  • 301206 Pharmakologie
  • 104015 Organische Chemie