Schlüsselwörter
(Englisch)
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drug discovery; identification of binding interactions; chemical biology; natural products
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Forschungsprogramme
(Englisch)
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COST-Action CM0804 - Chemical Biology with Natural Products
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Kurzbeschreibung
(Englisch)
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The GABAA receptors are the major inhibitory neurotransmitter receptor in the mammalian brain. They are involved in sleep behavior and sedation. We have recently identified a novel endogenous beta2 subunit-specific binding site in GABAA receptors for the endocannabinoid 2-AG. 2-AG induces positive allosteric effects in the presence of low GABA concentrations as they are found in extrasynaptic regions in the CNS (submitted for publication). Preliminary evidence from animal studies clearly suggests that 2-AG is a physiological modulator of GABAA receptors and synergizes with neurosteroids. In order to explore the binding site we aim to screen for small organic compounds, in particular natural products, which com-petitively bind to this 2-AG binding site in GABAAreceptors in order to develop tool compounds (antagonists and agonists) in order to assess the possibility for drug discovery. Both pharmacophore modeling (structure based) and random screening approaches will be used. Given that there are many lipophilic natural products that bind to allosteric binding sites so far not elucidated, we intend to focus on such compounds for screening first. The development of ligands for the 2-AG binding site in GABAA receptors will lead to the generation of lead compounds that can be evaluated in animal models. Agonists are expected to reduce hyperactivity and improve sleeping behavior, while antagonists may increase motility and motivation.
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Weitere Hinweise und Angaben
(Englisch)
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Full name of research-institution/enterprise: Universität Bern Institute of Biochemistry and Molecular Medicine
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Partner und Internationale Organisationen
(Englisch)
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BE, CH, CZ, DE, DK, EL, ES, FI, FR, IE, IT, LT, LV, NO, PT, RO, RS, SE, TR, UK
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Abstract
(Englisch)
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GABAA receptors are ligand-gated chloride channels and the major inhibitory receptors in the brain. GABAA receptors control fundamental neurophysiological processes like sleep, anxiety and locomotion. The endocannabinoid 2-arachidonoylglycerol (2-AG) is a major lipid in brain and interacts with a novel binding site in the beta-2 subunit of GABAA receptors. Intrestingly, 2-AG is a positive allosteric modulator of GABA and acts in concert with neurosteroids, thus providing novel opportunities for drug discovery. Although we have already obtained some physiological evidence for the role of 2-AG in behaviour, using beta-2 knockout mice, pharmacological tools (agonists or antagonists) are lacking. In this project we aim to identify ligands that competitively target this binding site, using different screening approaches. In addition to the rational approach mapping the 2-AG bdinding site through selective exchange of amino acids (loss of function mutations) and homology modeling, we aim to establish a robust functional assay. Such an assay in which the release and activation of GABAA receptors could be monitored in a single cell line (in addition to electrophysiology using Xenopus oocytes) will enable us to study a range of different ligands and also screen small molecule libraries, including natural products. Moreover, the synergy between differen allosteric modulators could be studied. The aim is to find an organic molecule that mimics(or antagonizes) the action of the endocannabinoid 2-AG but has more favorable biophysical properties. The identification of a lead compound will provide a novel tool to better study the proposed endocannabinoid-GABA interaction.
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Datenbankreferenzen
(Englisch)
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C10.0143
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