beta-Lumicolchicine interacts with the benzodiazepine binding site to potentiate GABAA receptor-mediated currents.
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.
Mihic
S J
SJ
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Whatley
V J
VJ
McQuilkin
S J
SJ
Harris
R A
RA
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008162:Lumicolchicines / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002712:Chlorides; D018076:DNA, Complementary; D008162:Lumicolchicines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam