[Zurück]


Vorträge und Posterpräsentationen (ohne Tagungsband-Eintrag):

M.T. Iorio, S. Rehman, K. Bampali, P. Scholze, F. Steudle, M. Ernst, M.D. Mihovilovic:
"Synthesis of novel ring structures as GABAA receptor ligands";
Vortrag: 15th Meeting of the Austrian Neuroscience Association, Klosterneuburg; 24.09.2017 - 26.09.2017.



Kurzfassung englisch:
Background: GABAA receptors belong to the superfamily of pentameric ligand-gated ion channels with high subunit diversity, where the most common receptors are composed of two β, two α and one γ subunit. These receptors are targets of many clinically relevant drugs such as benzodiazepines, barbiturates and steroids for the treatment of anxiety, depression and epilepsy. Benzodiazepines act as positive allosteric modulators at the interface between α and γ subunits in the extracellular domain of GABAA receptors. Diverse other allosteric binding sites have been described on these receptors, on which a wide range of small molecule scaffolds act as allosteric modulators. Based on some distantly related lead compounds we synthesized an exploratory library for SAR (structure-activity relationship) screening in GABAA receptors. Methods: Electrophysiological have been performed with cells expressing recombinant GABAA receptor subtypes. The compounds were synthesized according to literature procedures. The reactions were monitored via thin layer chromatography, and the compounds were purified via column chromatography or recrystallization. For the analysis 1H and 13C NMR spectra were recorded and the structure of the compounds was confirmed with X-ray analysis. Results: Preliminary electrophysiology data suggests that compounds containing the ester group in R2 are marginally active in δ containing GABAA receptors whereas robust positive allosteric modulation was observed in compounds containing carboxylic acid group in the R2. Screening in the binary receptors revealed modulatory activity as well. Discussion: Here we present a series of indole-derivatives which show modulation on GABAA receptors. Since the esterification of R2 was not tolerated, we will focus on the carboxylic acid containing compounds as these showed more promising results. In two other positions on the molecule, a range of substituents is tolerated as well and leads to small changes in potency which will be considered in further experiments. In order to define a functional selectivity profile we will test these compounds on receptors with different subunit combinations.

Erstellt aus der Publikationsdatenbank der Technischen Universität Wien.