β-Lumicolchicine Interacts with the Benzodiazepine Binding Site to Potentiate GABAA Receptor-Mediated Currents |
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Authors: | S John Mihic Valerie J Whatley Susan J McQuilkin R Adron Harris† |
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Institution: | Department of Pharmacology, University of Colorado Health Sciences Center;;Denver Veterans Administration Medical Center, Denver, Colorado, U.S.A. |
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Abstract: | Abstract: An analogue of colchicine,β-lumicolchicine, does not bind tubulin or disrupt microtubules. However, this compound is not pharmacologically completely inactive. β-Lumicolchicine was found to competitively inhibit 3H]flunitrazepam binding and to enhance muscimol-stimulated 36Cr-uptake in mouse cerebral cortical microsacs. It also markedly potentiated GABA responses in Xenopusoocytes expressing human α1β2γ2S, but not α1β2, GABAA receptor subunits; this potentiation was reversed by the benzodiazepine receptor antagonist flumazenil. These results strongly suggest a direct effect of β-Lumicolchicine on the GABAA receptor/chloride channel complex and caution that it possesses pharmacological effects, despite its inability to disrupt microtubules. Furthermore, β-Lumicolchicine is structurally unrelated to benzodiazepines or quinolines and may provide a novel approach to the synthesis of ligands for this receptor. |
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Keywords: | GABA Benzodiazepine receptor β-Lumicolchicine Xenopusoocytes Rat brain microsacs |
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