title: Bisindole alkaloids from Strychnos guianensis are effective antagonists of nicotinic acetylcholine receptors in cultured human TE671 cells.
abstract: Several mono- and bisindole quaternary alkaloids isolated from the stem bark of Strychnos guianensis have recently been shown to be effective blockers of neuromuscular transmission in mice. In this study, we used a human clonal cell line (TE671) expressing muscle-type nicotinic acetylcholine receptors. The agonist carbamylcholine activated a receptor-mediated (86)Rb(+) efflux and this activation was antagonized by the indole alkaloids, the most active being bisindole bisquaternary compounds. The most effective antagonist, guiachrysine, had an IC(50) around 0.43 microM in the presence of 0.5 mM carbamylcholine, compared to 0.16 microM for d-tubocurarine, the most potent curarizing alkaloid. Guiaflavine and 5',6'-dehydroguiaflavine were slightly less effective. Monoindole compounds were 10 to 100 times less potent than bisindole alkaloids. Kinetic analysis showed that the inhibition of the carbamylcholine-dependent (86)Rb(+) efflux by guiaflavine was of mixed competitive and uncompetitive type. The competitive component (K(I)=0.21 microM) is presumably due to binding at the acetylcholine site, while the uncompetitive component (K'(I)=0.92 microM) may be due to open channel block.
authors.affiliation: Center for Cellular and Molecular Neurobiology, University of Liège, place Delcour, 17, 4020 Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Wins
authors.forename: Ilca
authors.initials: I
authors.lastname: Margineanu
authors.forename: Jacques
authors.initials: J
authors.lastname: Penelle
authors.forename: Luc
authors.initials: L
authors.lastname: Angenot
authors.forename: Thierry
authors.initials: T
authors.lastname: Grisar
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
mesh_terms: D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D006801:Humans; D026121:Indole Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D024301:Plant Bark / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000187:drug effects*; D031451:Strychnos / Q000737:chemistry*; D013997:Time Factors
chemical_list: D018679:Cholinergic Agonists; D026121:Indole Alkaloids; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D002217:Carbachol