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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Jiang, Ruotian Brouillard, Raymond Goeldner, Maurice Martz, Adeline Specht, Alexandre Miyamoto, Akiko De Carvalho, Lia Prado Nielsen, Mogens Ishibashi, Hitoshi Kueny-stotz, Marie Nabekura, Junichi Chassaing, Stefan Grutter, Thomas |
Description | Author Affiliation: Jiang R ( Laboratoire de Biophysicochimie des Récepteurs Canaux, UMR 7199 CNRS, Conception et Application de Molécules Bioactives, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.) |
Abstract | BACKGROUND AND PURPOSE: Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABA(A) receptors (GABA(A)Rs). We previously reported that trans-6,4'-dimethoxyretrochalcone (Rc-OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABA(A)Rs. Here, we evaluate the functional modulations of Rc-OMe, along with two other synthetic derivatives trans-6-bromo-4'-methoxyretrochalcone (Rc-Br) and 4,3'-dimethoxychalcone (Ch-OMe) on GABA(A)Rs. EXPERIMENTAL APPROACH: Whole-cell patch-clamp recordings were made to determine the effects of these derivatives on GABA(A)Rs expressed in HEK-293 cells and in hippocampal CA1 pyramidal and thalamic neurones from rat brain. KEY RESULTS: Rc-OMe strongly potentiated GABA-evoked currents at recombinant (1-4)ß(2)γ(2s) and (4)ß(3)δ receptors but much less at (1)ß(2) and (4)ß(3). Rc-Br and Ch-OMe potentiated GABA-evoked currents at (1)ß(2)γ(2s). The potentiation by Rc-OMe was only reduced at (1)H101Rß(2)γ(2s) and (1)ß(2)N265Sγ(2s), mutations known to abolish the potentiation by diazepam and loreclezole respectively. The modulation of Rc-OMe and pentobarbital as well as by Rc-OMe and the neurosteroid 3 ,21-dihydroxy-5 -pregnan-20-one was supra-additive. Rc-OMe modulation exhibited no apparent voltage-dependence, but was markedly dependent on GABA concentration. In neurones, Rc-Br slowed the decay of spontaneous inhibitory postsynaptic currents and both Rc-OMe and Rc-Br positively modulated synaptic and extrasynaptic diazepam-insensitive GABA(A)Rs. CONCLUSIONS AND IMPLICATIONS: The trans-retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABA(A)Rs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABA(A)-related disorders in vivo. |
ISSN | 00071188 |
e-ISSN | 14765381 |
Journal | British Journal of Pharmacology |
Issue Number | 6 |
Volume Number | 162 |
Language | English |
Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
Publisher Date | 2011-03-01 |
Publisher Place | Great Britain (UK) |
Access Restriction | Open |
Subject Keyword | CA1 Region, Hippocampal Drug Effects Chalcones Pharmacology Pyramidal Cells Receptors, GABA-A Metabolism Ventral Thalamic Nuclei Animals Benzodiazepines Chemical Synthesis HEK293 Cells Neurotransmitter Agents Patch-Clamp Techniques Plasmids Rats, Wistar Stereoisomerism Gamma-Aminobutyric Acid Research Support, Non-U.S. Gov't |
Content Type | Text |
Resource Type | Article |
Subject | Pharmacology |
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