Valerenic acid-en route to a CNS active drug

Valerenic acid (VA, a major constituent of Valeriana officinalis rhizome) has been recently identified as highly selective modulator of GABA type A (GABAA ) receptors. The applicants have shown that VA selectively modulates receptors that contain ß 2 - or ß 3 - subunits. Replacing the ß 2/3-subunits by a ß 1 -subunit drastically reduced the modulation of GABA-induced chloride currents (IGABA) by VA (Khom et al. 2007). Introducing the point mutation ß 2 N265S abolished the modulatory activity of VA. ß 2/3-subunit specificity of VA suggests (in analogy to the action of loreclezole) potential antiepileptic effects. Furthermore, in vivo studies of Benke et al. (2008) revealed that VA exerts anxiolytic activity with high potencies in the elevated plus maze and the light/dark choice test in wild type mice. In ß 3 -subunit (N265M) point-mutated mice the anxiolytic activity of valerenic acid was absent. These findings suggest that VA (and its derivatives) may be interesting drug candidates. The applicants have therefore recently described the first de novo synthesis of VA (Ramharter and Mulzer, 2009). To promote a potential use of VA (and its derivatives) as novel CNS active drugs the University of Vienna has applied for patent protection of the synthesis. The current synthesis, however, suffers from several drawbacks such as the use of expensive reagents, many steps and low yields. To enable the characterization of these molecules as potential drug candidates larger quantities of the molecules are required. We aim therefore to optimize the synthesis with respect to the number of steps, simplicity and scalability of the reactions and the price of the starting materials, reagents and catalysts. The aimed in vitro and in vivo (behavioural) studies with VA (and its derivatives) will enable a more detailed pharmacological characterisation of these molecules. This interdisciplinary collaboration will thus facilitate the application of the basic research in both institutions.

?-Aminobutyric acid (GABA) is the principle inhibitory neurotransmitter in the mammalian brain. GABA is present in 20-50 % of the cerebral cortex synapses. Dysfunction of the GABAergic system is associated with a multitude of neurological disorders including insomnia, anxiety, panic and mood disorders, alcoholism and epilepsy. A promising biological target are GABAA channels which are modulated by numerous structurally distinct substances including clinically important drugs as BZDs, barbiturates and various general anaesthetics, but also by some natural products. Thus, valerenic acid (VA) has recently been shown to selectively modulate GABAA receptor subtypes. Thus the aim of this translational project was the development of a robust, scalable and economic total synthesis and broad biological testing of VA and derivatives thereof to obtain lead structures for later drug development. In a 3.5 year cooperation between the Department of Pharmacology at Uni Vienna (S. Hering) and the Institute of Organic Chemistry at Uni Vienna (J Mulzer) about 40 VA--derivatives have been synthesized by the Mulzer group and subjected to electrophysiological cell tests and later mouse experiments by the Hering group. In the end some promising drug candidates have been identified which have some advantages over the parent natural compounds.