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G. Pototschnig, S. Hering, M.D. Mihovilovic:
"Scaffold optimization of the GABAA receptor ligand Valerenic acid";
Poster: 16th Tetrahedron Symposium, Berlin; 16.06.2015 - 19.06.2015.

Anxiety and panic disorders are amongst the most common mental diseases worldwide.
Most effectively, these diseases 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 subtype selective allosteric ligand on the GABAA receptor.1 The highly pronounced
selectivity for β2/3 over β1 subunits allows for addressing anxiety rather than sedation in animal
models.2 Therefore, Valerenic acid could serve as alternative for benzodiazepines for the
treatment of anxiety.
To gain insight into the so far unknown binding mode and mode of action of Valerenic acid
derived GABAA receptor ligands different regions of the complex original structure were
modified (Figure 1).
Fig. 1: Modifications of the original Valerenic acid structure.
Based on the total synthesis of Valerenic acid3, a set of compounds was synthesized and
biologically evaluated via electrophysiology.
Results from the above mentioned structural alterations, in regions and functionalities, could
give insight in the ligand - receptor interaction and elucidate structural motifs necessary for
binding.
We plan to further optimize the structure in terms of synthetic feasibility and biological activity.
REFERENCES
1. Khom, S.; Baburin, I.; Timin, E.; Hohaus, A.; Trauner. G.; Kopp, B.; Hering, S.
Neuropharmacology, 2007, 53, 178-187.
2. Khom, S.; Strommer, B.; Ramharter, J.; Schwarz, T.; Schwarzer, C.; Erker, T.; Ecker, G. F.;
Mulzer, J.; Hering, S., Br J Pharmacol 2010, 161, 65-78.
3. Ramharter, J.; Mulzer, J. Organic Letters, 2009, 11, 1151-1153.
Keywords: Valerenic acid, GABAA receptor, anxiety