Lead development for ligand gated ion channels
Please notice these positions are no longer vacant.

Structural modification of natural compound GABAA receptor modulators
(in collaboration with S. Hering, M. Ernst & G. Ecker)

Natural products have been historically an important source for drugs and up to now provide structurally unique leads and inspiration for medicinal chemistry. Piperine has recently been identified as a GABAA receptor modulator in addition to the known interaction with TRPV1 receptors (Zaugg et al. 2010). Piperine will serve as model case study to elucidate the target (GABAA vs. TRPV1) specific properties of the molecule. Consequently, a focus of this project involves the structural modification of piperine and generation of an appropriate library of derivatives. Such analogs to piperine will be assessed for potency and efficiency on GABAA and TRPV1 receptors in close cooperation with the group of S. Hering. In addition, sub-type specitivity of novel ligands on various GABAA receptors will be studied in collaboration with the group of M. Ernst.

Preparation of compound libraries will be based on ample existing expertise in the area of (het)aryl-het(aryl) metal-assisted cross-coupling strategies. Additionally, it will be largely facilitated by the automation-assisted synthetic instrumentation in the laboratory of MDM, including automated batch and stopped-flow microwaves, flow-reactors for high-pressure and catalyzed reactions, and a fully automated flow-chemistry synthetic robot capable to conduct multi-step synthetic sequences (in combination with efficient high throughput purification systems on MPLC and prep-HPLC). Consequently, repetitive synthetic efforts will be conducted by automated devices, maximizing the creativity in structure modifications elaborated by the graduate student.

The particular research program for the PhD candidate will involve state-of-the-art training in automation-assisted organic synthesis, in particular focusing on metal-assisted strategies. In addition, receptor binding and bio-efficacy studies will be conducted in close cooperation with the groups of S. Hering and M. Ernst, taking advantage of the available instrumentation in these laboratories. It is a particular aim, to also establish a pharmacophore model for the target compounds together with the group of G. Ecker. Typically, the required expertise of a PhD candidate will involve a strong background in (bio)organic chemistry (esp. synthesis, purification, and characterization of organic compounds) with certain expertise in biochemical experimentation (enzymology, cellculture) and pharmacology. The research program will offer particular training units to enable the candidate to work autonomously with all required techniques.

Scaffold optimization of GABAA receptor ligands
(in collaboration with S. Hering & G. Ecker)

Recently, valerenic acid - a chiral bicyclic terpenoidal natural compound - was identified as a subtype specific GABAA receptor ligand (Khom et al. 2010). We aim to start from this principal scaffold and identify the critical structural motifs associated to biological activity. Based on this concept, a first generation of simplified structures will be outlined and synthesized, followed by biological assessment (in cooperation with S. Hering). Based on the results of ligand-receptor binding studies and biological efficacy in cell culture (determined primarily via electrophysiological changes), a computer model will be generated and subsequent generations of synthetic targets will be developed. This part of the project will take advantage of the high degree of instrumentation of the synthetic group, allowing for rapid generation of focused compound libraries.

It is expected to ultimately generate a computational model for identifying key structural elements related to particular binding properties of the above outlined starting point structures as well as the compound collection prepared within this program. Taken together with biological data in vitro and in vivo, this should allow for a significantly improved understanding of this receptor type and provide a knowledge base for future ligand design. Typically, the required expertise of a PhD candidate will involve a strong background in (bio)organic chemistry (including asymmetric synthesis) with certain expertise in biochemical experimentation to also enable biological screening work (however, this will be strongly supported by existing personnel in the Hering lab). In addition, this project involves aspects of computational chemistry, and a particular training program will be implemented in the Ecker team up-front of the experimental work to allow for development and tuning of the required computer models.