beta-Lumicolchicine interacts with the benzodiazepine binding site to potentiate GABAA receptor-mediated currents

• Published in: Journal of neurochemistry Vol. 62; no. 5; p. 1790
• Main Authors: Mihic, S J, Whatley, V J, McQuilkin, S J, Harris, R A
• Format: Journal Article
• Language: English
• Published: England 01.05.1994
• Subjects: Animals; Benzodiazepines - metabolism; Binding Sites; Binding, Competitive; Cerebral Cortex - metabolism; Chlorides - metabolism; DNA, Complementary - metabolism; Flumazenil - pharmacology; Flunitrazepam - metabolism; gamma-Aminobutyric Acid - pharmacology; Humans; Kinetics; Lumicolchicines - metabolism; Lumicolchicines - pharmacology; Mice; Mice, Inbred ICR; Oocytes - drug effects; Oocytes - physiology; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; Receptors, GABA-A - physiology; Xenopus laevis
• ISSN: 0022-3042
• DOI: 10.1046/j.1471-4159.1994.62051790.x

An analogue of colchicine, beta-lumicolchicine, does not bind tubulin or disrupt microtubules. However, this compound is not pharmacologically completely inactive. beta-Lumicolchicine was found to competitively inhibit [3H]flunitrazepam binding and to enhance muscimol-stimulated 36Cl- uptake in mouse cerebral cortical microsacs. It also markedly potentiated GABA responses in Xenopus oocytes expressing human alpha 1 beta 2 gamma 2S, but not alpha 1 beta 2, GABAA receptor subunits; this potentiation was reversed by the benzodiazepine receptor antagonist flumazenil. These results strongly suggest a direct effect of beta-lumicolchicine on the GABAA receptor/chloride channel complex and caution that it possesses pharmacological effects, despite its inability to disrupt microtubules. Furthermore, beta-lumicolchicine is structurally unrelated to benzodiazepines or quinolines and may provide a novel approach to the synthesis of ligands for this receptor.