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D. Cintulova, G. Pototschnig, D. Lugner, M. Stadler, S. Hering, M.D. Mihovilovic:
"Scaffold Optimization of the GABAA Receptor Ligand Valerenic Acid";
Poster: 17th Blue Danube Symposium on Heterocyclic Chemistry, Linz; 30.08.2017 - 02.09.2017.

Anxiety and panic disorders are amongst the most common mental diseases worldwide. Most effectively, they are treated with benzodiazepines. However, these compounds are known to cause severe side effects like confusion, fatigue and drug addiction. Valerenic acid, a sesquiterpenoidal compound isolated from roots of Valeriana officinalis, acts as a subtype selective allosteric ligand on GABAA receptor. The highly pronounced selectivity for β2/3 over β1 subunit allows for addressing anxiety rather than sedation in animal models. Therefore, valerenic acid could serve as a lead structure for alternatives to benzodiazepines in the treatment of anxiety.1
Based on the already published total synthesis of valerenic acid 2, a modified synthetic approach for modification of the core was established. The modifications included removing the methyl group on the 6-membered ring in the original scaffold and replacement of the natural compound´s bicycle core towards sterically more demanding derivatives. The cyclopentane ring in the original scaffold has been replaced by cyclohexane. This replacement led to the identification of a ligand with novel subtype selectivity for GABAA receptors bearing β1 subunits.

One of the key elements of the literature known approach is the definition of one stereocenter via a kinetic resolution of a secondary alcohol at a very early stage of the synthetic pathway. This enzymatic kinetic resolution is accompanied with the loss of a minimum of 50% of the material. That´s why the enzymatic process was combined with an in situ racemization that renders the transformation dynamic. A screening for different ring sizes and double bond substitutions was performed as a proof of concept.

GABAA receptor, valerenic acid, scaffold optimization

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