Novel GABA-A receptor modulators: Molecular mechanism and binding sites
Please notice these positions are no longer vacant.

Structure-activity studies with natural compound GABAA receptor modulators and chemical compound libraries
The occurrence of modulators of GABAA-receptors in plant extracts is high. In collaboration with the group of Prof. Hamburger (Department of Pharmaceutical Biology, University of Basel) we aim to identify potential lead structures. A Xenopus oocytes voltage clamp system is integrated into a miniaturized drug discovery platform combining HPLC separation of plant extracts and fungi with microfractionation for bioassay, on-line spectroscopy, and off-line NMR with a dedicated microprobe. The PhD student will perform the isolation and structural identification of natural product GABAA receptor modulators in Basel. The interaction with different GABAA receptor subtypes will be analyzed in Xenopus oocytes under voltage clamp conditions. Site-directed mutagenesis and functional studies will enable insights into the location the binding pockets of these compounds. Chemical modification of these compounds and pharmacological studies will provide insights into structure activity relationships.

In vivo characterisation of novel GABAA receptor ligands
γ-aminobutyric acid (GABA) mediates fast inhibitory synaptic neurotransmission by interacting with ionotropic GABA type A (GABAA) receptors. Impairment of the GABAergic inhibitory control is associated with multiple neurological disorders including anxiety, insomnia or epilepsy. GABAA receptors are therefore important drug targets. In vivo studies on mouse models will be performed to assess the therapeutic potential and potential side effects of novel GABAA receptor modulators. We focus on characterization of novel ligands identified in TCM and other plants as well as on compounds identified in chemical libraries and their derivatives. Standard behavioral tests such as elevated plus maze, open field, Rota-Rod will be part of the project. Effects on seizure threshold will be estimated to get insights into potential antiepileptic actions. Studies addressing the pharmacokinetics, penetration of the blood-brain barrier and metabolism will be part of the project.