Prof. Marko Mihovilovic

Synthesis of novel ring structures as GABAA receptor ligands with functional selectivity for sleep promoting receptors.
Following the recent discovery of a new modulatory binding site on the α+/β- interface of GABAA receptors, pyrazoloquinolinones have been extensively investigated as ligands (Varagic et al.). Due to our continuing interest in GABAA receptor modulators we aim to identify ligands with a novel chemical scaffolds. Along this line, we plan to conduct scaffold-hops towards diverse heterocyclic core structures. This would lead to a changed molecule geometry and physico-chemical properties while retaining functional groups known to be essential for receptor binding. Preliminary studies suggest that such new scaffolds may display significantly modified sub-type selectivity towards modulation of sleep promoting receptors. Workplan: In this project, a library of scaffold-modified structures will be prepared in order to investigate this compound class and identify SAR. Furthermore, synthetic studies will involve detailed investigations of novel mechanisms and cyclization reaction as well as optimization of synthetic routes towards target structures. Networking: The project is a joint effort of the Mihovilovic, Ernst and Ecker labs and thus three PhD students are planned to be involved. Our lab will work in close cooperation with the Ecker lab, where a PhD student will perform ligand based modelling and compound design. The Ernst lab will perform all pharmacological characterizations of the target compounds. Methods: The student will learn the full repertoire of state-of-the-art synthetic organic chemistry as well as modern analytical methods including NMR, HPLC, GC-MS, LC-MS-NMR. Furthermore the student will be trained in interpretation of biological data in close cooperation with the project partners.


Enantioselective Synthesis of Configurationally Stabilized Methcathinones for the Investigation of Monoamine Transporters.
Methcathinones are usually prepared and tested as racemic mixtures of enantiomers. We hypothesized that the single enantiomers might exhibit very different effects at their protein targets. Thus, enantiopure methcathinones would be highly attractive tool-compounds for the investigation of the function of monoamine transporters on a molecular level. In a pilot study we have prepared enantioenriched methcathinones as inhibitors of MATs. In a 5-HT uptake inhibition assay e.g. (R)- and (S)-mephedrone showed significantly different EC50 values, thus supporting our initial hypothesis. The methods currently availiable for the enantioselective synthesis of methcathinones suffer from various drawbacks, such as uncontrollable regioselectivity or decay of enantiomeric excess. Therefore a improved method would be desirable. A serious complication of efforts aimed at the investigation of enatiopure cathinones is their propensity to undergo epimerization under neutral or basic conditions. We hypothesize, that epimerization will be rendered impossible if the alpha-position was blocked. We expect, that introduction of a methyl-, fluoro- or chloro-substituent would sufficiently stabililze the chiral center. Workplan: In this project, the current method for the enantioselective and regioselective synthesis of methcathinones will be improved. Furthermore a method for the enantioselective alpha-halogenation and -alkylation of cathinones will be developed. These methods will be employed to synthesize a library of (stabilized) methcathinones as tool-compounds. Networking: The project is a joint effort of the Mihovilovic, Sitte and Ecker labs and thus three PhD students will be involved. Compound testing and pharmacological charaterization of compounds will be performed at the Sitte lab. Our lab will work in close cooperation Ecker group, where a PhD student will conduct docking studies of the target compounds at the transporter protein. Methods: The student will learn the full repertoire of state-of-the-art synthetic organic chemistry as well as modern analytical methods including NMR, HPLC, GC-MS, LC-MS-NMR. Furthermore the student will be trained in interpretation of biological data in close cooperation with the project partners.