Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Abstract

Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3-3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine ([3H]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O-desmethylibogaine, its metabolism resistant analog O-t-butyl-O-desmethylibogaine, the iboga alkaloids (±)-ibogamine, (±)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1-methylindol-2-yl)-8-methyl-8- azabicyclo[3.2.1]octane (RS 075194-190), exo-3-(1-methylindol-2-yl)-8-methyl-8- azabicyclo[3.2.1]octane (RS 075237-190) and endo-3-(indol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [3H]MK-801 binding (K(i) = ~1.2 μM), whilst the compounds with the greatest structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl-O-desmethylibogaine were less potent (K(i) = ~5.5 and 179.0 μM, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl-O-desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.