Epilepsy represents a very common neurological disease entity worldwide, accounting for more than 50 million patients. Current antiepileptic drugs (AEDs) are efficacious with only about 2/3 of all patients, and about 30% of cases have - or develop - drug-resistance, highlighting the urgency for the discovery of novel medication. Small molecule natural products are an unrivaled and inexhaustible source for the development of new drugs and essential tools for biomedical research as probes of biological functions. The consortium of the Department of Pharmacology and Toxicology (University of Vienna), the Department of Neurophysiology and Neuropharmacology (Medical University of Vienna) and the Department of Pharmaceutical Chemistry (University of Vienna) aims to identify and develop novel ion channel modulators based on natural product analogues and their derivatives so that they serve as scaffolds for the development of AEDs with improved properties. Targets for most of the licensed AEDs are voltage-gated Na+, K+ and Ca2+ channels as well as the neurotransmitters glutamate and GABA in combination with their cognate receptors. The applicants have developed novel GABAA receptor modulators and, additionally, revealed that the Kv7 channel opening AED retigabine is also a subtype-selective GABAA receptor modulator. Accordingly, this project will use the structures of valerenic acid (VA) and dehydroabietic acid (DHAA), recently described modulators of GABAA receptors and K+ channels, as starting points for the development of novel AEDs that simultaneously target these receptors and Kv7 as well as other K+ channels. To do so, pharmacophore models will be applied to synthesize small molecule libraries, and recombinant as well as native ion channels will be used to characterize these agents, which will then be tested for actions on synaptic transmission. Primary cell cultures and brain slices as in vitro approaches will be complemented with in vivo models of epilepsies, and finally drug effects will be analyzed using therapy-resistant epileptic human tissue. With this set of diversified and complementary methods at hand at the two universities (Fig. 1), several rounds of lead optimization followed by retesting of the resulting new molecules can be executed to design novel structures for AEDs with improved efficacy (see Fig. 2 for preliminary results).