Identification of dihydrostilbenes in Pholidota chinensis as a new scaffold for GABAA receptor modulators
| Autor: | Steffen Hering, Matthias Hamburger, Maria De Mieri, Evelyn A. Jähne, Diana C. Rueda, Melanie Raith, Angela Schöffmann |
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| Rok vydání: | 2013 |
| Předmět: |
Pterostilbene
Patch-Clamp Techniques Stereochemistry Voltage clamp Protein subunit Clinical Biochemistry Xenopus Pharmaceutical Science Biochemistry High-performance liquid chromatography Plant Roots law.invention chemistry.chemical_compound Xenopus laevis law Drug Discovery Stilbenes Animals Receptor Orchidaceae Molecular Biology biology Plant Stems GABAA receptor Plant Extracts Organic Chemistry biology.organism_classification Receptors GABA-A Protein Subunits chemistry Recombinant DNA Oocytes Molecular Medicine |
| Zdroj: | Bioorganic and Medicinal Chemistry |
| ISSN: | 1464-3391 |
| Popis: | A dichloromethane extract of stems and roots of Pholidota chinensis (Orchidaceae) enhanced GABA induced chloride currents (IGABA) by 132.75 ± 36.69 when tested at 100 µg/mL in a two microelectrode voltage clamp assay on Xenopus laevis oocytes expressing recombinant a1ß2?2S GABAA receptors. By means of an HPLC based activity profiling approach the three structurally related stilbenoids coelonin (1) batatasin III (2) and pholidotol D (3) were identified in the active fractions of the extract. Dihydrostilbene 2 enhanced IGABA by 1512.19 ± 176.47 at 300 µM with an EC50 of 52.51 ± 16.96 µM while compounds 1 and 3 showed much lower activity. The relevance of conformational flexibility for receptor modulation by stilbenoids was confirmed with a series of 13 commercially available stilbenes and their corresponding semisynthetic dihydro derivatives. Dihydrostilbenes showed higher activity in the oocyte assay than their corresponding stilbenes. The dihydro derivatives of tetramethoxy piceatannol (12) and pterostilbene (20) were the most active among these derivatives but they showed lower efficiencies than compound 2. Batatasin III (2) showed high efficiency but no significant subunit specificity when tested on the receptor subtypes a1ß2?2s a2ß2?2s a 3ß2?2s a4ß 2?2s a5ß2? 2s a1ß1?2s and a1ß3?2s. Dihydrostilbenes represent a new scaffold for GABAA receptor modulators. © 2014 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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