Valerenic acid derivatives as novel subunit‐selective GABA_A receptor ligands –in vitro and in vivo characterization

Abstract

BACKGROUND AND PURPOSE Subunit‐specific modulators of γ‐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 β2/3 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 GABAA 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 µM) on α1β3 receptors. Higher efficacy and potency of VA‐A were also observed on α1β2γ2s and α3β3γ2s 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 β3 subunit containing GABAA receptors for development of anxiolytics.

<b><i>Valeriana officinalis</i></b> Root Extract Modulates Cortical Excitatory Circuits in Humans

“…In contrast, NE system modulators enhance ICF [30]. These mechanisms are remarkably consistent with the premise that VE, and, particularly valerenic acid, the main component of VE, allosterically modulate GABA A receptors and, in this way, are thought to induce anxiolytic activity [31,32,33,34]. A similar modulatory effect on the GABA A channel was demonstrated for other components of the VE such as alerenol, 6-methylapigenin, and linarin [35,36].…”

Identification of novel positive allosteric modulators and null modulators at the GABAA receptor α+β− interface

“…To show that this is a specific effect, we also co-applied these compounds with modulatory ligands that do not elicit modulation via the a+/b-site (Ramerstorfer et al, 2011). As expected, the GABA potentiating effects of ROD 188 (Thomet et al, 2000; Figure 3B) or of valerenic acid amide (Khom et al, 2010; data not shown) remained unaltered in the presence of compounds 23, 25, 27 or 33. These data indicated that these compounds were able to specifically block the effects of compound 11 mediated via the a1+b3-binding site without interfering with the action of compounds binding to an unrelated binding site of a1b3 receptors.…”

Positive GABAA Receptor Modulators from Acorus calamus and Structural Analysis of (+)-Dioxosarcoguaiacol by 1D and 2D NMR and Molecular Modeling

“…Valerenic acid from Valeriana officinalis roots is a β 2/3 -subunit-specific positive allosteric modulator 44,48 with anxiolytic effects in vivo. 48,49 This compound has served as a new scaffold for GABA A receptor ligands. 49,50 Among the compounds identified by the profiling of Acorus extract, the simple phenylpropanoid β-asarone (1) induced the highest potentiation of I GABA (1200% ± 163% with an EC 50 of 171.5 ± 34.6 μM).…”

“…48,49 This compound has served as a new scaffold for GABA A receptor ligands. 49,50 Among the compounds identified by the profiling of Acorus extract, the simple phenylpropanoid β-asarone (1) induced the highest potentiation of I GABA (1200% ± 163% with an EC 50 of 171.5 ± 34.6 μM). Its efficiency at a GABA EC 5-10 was significantly Zaugg et al Page 4 higher than that of known GABA A receptor modulators such as benzodiazepines (triazolam: 253% ± 12%, midazolam: 342% ± 64%, clotiazepam: 260% ± 27%) 51 or natural products such as valerenic acid (400% ± 78%).…”