title: Study of the interaction of antiplasmodial strychnine derivatives with the glycine receptor.
abstract: Strychnos icaja Baill. (Loganiaceae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric indolomonoterpenic alkaloids with antiplasmodial properties have been isolated from its rootbark. Since these alkaloids are derivatives of strychnine, it was important, in view of their potential use as antimalarial drugs, to assess their possible convulsant strychnine-like properties. In that regard, their interaction with the strychnine-sensitive glycine receptor was investigated by whole-cell patch-clamp recordings on glycine-gated currents in mouse spinal cord neurons in culture and by [(3)H]strychnine competition assays on membranes from adult rat spinal cord. These experiments were carried out on sungucine (leading compound of the chemical class) and on the antiplasmodial strychnogucine B (dimeric) and strychnohexamine (trimeric). In comparison with strychnine, all compounds interact with a very poor efficacy and only at concentrations >1 microM with both [(3)H]strychnine binding and glycine-gated currents. Furthermore, the effects of strychnine and protostrychnine, a monomeric alkaloid (without antiplasmodial activity) also isolated from S. icaja and differing from strychnine only by a cycle opening, were compared in the same way. The weak interaction of protostrychnine confirms the importance of the G cycle ring structure in strychnine for its binding to the glycine receptor and its antagonist properties.
authors.affiliation: Natural and Synthetic Drugs Research Center, Laboratory of Pharmacognosy, University of Liège, Belgium. g.phillippe@ulg.ac.be
authors.forename: Geneviève
authors.initials: G
authors.lastname: Philippe
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.forename: Luc
authors.initials: L
authors.lastname: Angenot
authors.forename: Michel
authors.initials: M
authors.lastname: Frédérich
authors.forename: Gustave
authors.initials: G
authors.lastname: Moonen
authors.forename: Monique
authors.initials: M
authors.lastname: Tits
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rigo
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D019281:Dimerization; D018756:GABA Antagonists / Q000494:pharmacology; D016488:Medicine, African Traditional; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology; D018408:Patch-Clamp Techniques; D018517:Plant Roots / Q000737:chemistry; D011724:Pyridazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018009:Receptors, Glycine / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000031:analogs & derivatives / Q000302:isolation & purification / Q000494:pharmacology*; D031451:Strychnos / Q000737:chemistry; D014316:Tritium
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D002227:Carbazoles; D018756:GABA Antagonists; D011724:Pyridazines; D018009:Receptors, Glycine; C428164:strychnogucine B; C472945:strychnohexamine; D014316:Tritium; C049853:gabazine; D013331:Strychnine