BETA-LUMICOLCHICINE INTERACTS WITH THE BENZODIAZEPINE BINDING-SITE TOPOTENTIATE GABA(A) RECEPTOR-MEDIATED CURRENTS

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