Valerenic acid (VA) - a β2/3-selective γ-aminobutyric acid (GABA) type A (GABAA) receptor modulator - displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here, we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared to saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax=972±69%, n=6, p<0.05) and α1 β2γ2S receptors (Emax=1119±72%, n=6, p<0.05) more efficaciously than VA (α1β3γ2S: VA: Emax=632±88%, n=9 vs. α1β2γ2S: VA: Emax=721±68%, n=6) displayed significantly more pronounced seizure threshold elevation than VA (saline-control: 40.4±1.4mg/kg PTZ vs. VA 10mg/kg: 49.0±1.8mg/kg PTZ vs. VA-A 3mg/kg: 57.9±1.9mg/kg PTZ, p<0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax=1043±57%, p<0.01, n=6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared to VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50=6.0±1.0μM, p<0.05; VA-TET: 0.3mg/kg: 47.3±0.5mg/kg PTZ vs. VA: 10mg/kg: 49.0±1.8mg/kg PTZ, p<0.05). At higher doses (≥10mg/kg), VA-A, VA-MA and VA-TET reduced locomotion. In contrast, unselective VA-derivatives induced anticonvulsive effects only at high doses (30mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA and VA-TET induce anticonvulsive effects at low doses (≤10mg/kg), while impairment of locomotion was observed at doses ≥10mg/kg.
- The American Society for Pharmacology and Experimental Therapeutics