NYU Conference on Ibogaine Nov 5-6, 1999

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STRUCTURALLY MODIFIED ANALOGUES OF IBOGAINE EXHIBIT DIFFERING AFFINITIES FOR NMDA RECEPTORS: IMPLICATIONS FOR ITS PUTATIVE ANTI-ADDICTIVE PROPERTIES.

Richard T. Layer, Phil Skolnick, Craig M. Bertha, Martin E. Kuehne and Piotr Popik*
Laboratory of Neuroscience, NIDDK, NIH, Bethesda, MD 20892, USA; *Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland

The psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties based on both preclinical and clinical studies. Previous data have suggested that the NMDA receptor may represent a locus for ibogaine's anti-addictive effects. Thus, of a series of ibogaine analogues tested, including the putative ibogaine metabolite des- methyl-ibogaine, its metabolism resistant analogue tert-butyl-ibogaine, 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), ibogaine had the highest potency to inhibit [3H]MK-801 binding to NMDA receptors (Ki = 1.2 EM). In contrast, des-methyl- ibogaine had the highest potency to inhibit [3H]U-69,593 binding to kappa opiate receptors in forebrain membranes from rat, mouse and guinea pig (IC50 = 0.28, 1.2 and 2.6 EM, respectively). In morphine- dependent mice, ibogaine, but not des-methyl-ibogaine or t-butyl- ibogaine was able to attenuate naloxone precipitated withdrawal jumping. These data suggest that inhibition of the expression of morphine dependence by ibogaine is related to its inhibitory effects at the NMDA receptor.

Piotr Popik
Institute of Pharmacology
Polish Academy of Sciences
12 Smetna Str., 31-343 Krakow, POLAND
Tel: (12) 374630
Fax: (12) 374500