Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation

Tamara Antonio, Steven R. Childers, Richard B. Rothman, Christina M. Dersch, Christine King, Martin Kuehne, William G. Bornmann, Amy J. Eshleman, Aaron Janowsky, Eric R. Simon, Maarten E A Reith, Kenneth Alper

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objective:The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of μ-opioid receptor (MOR)-related G proteins by iboga alkaloids.Methods:Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5́-O-(γ-thio)-triphosphate ([35S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices.Results And Significance:In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [35S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [35S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [35S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Original languageEnglish (US)
Article numbere77262
JournalPLoS One
Volume8
Issue number10
DOIs
StatePublished - Oct 16 2013

Fingerprint

Ibogaine
Tabernaemontana
narcotics
Opioid Receptors
GTP-Binding Proteins
Alkaloids
Opioid Analgesics
alkaloids
Chemical activation
Rats
agonists
mechanism of action
Autoradiography
rats
autoradiography
Brain
Cells
Membranes
Drug therapy
Detoxification

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Antonio, T., Childers, S. R., Rothman, R. B., Dersch, C. M., King, C., Kuehne, M., ... Alper, K. (2013). Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation. PLoS One, 8(10), [e77262]. https://doi.org/10.1371/journal.pone.0077262

Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation. / Antonio, Tamara; Childers, Steven R.; Rothman, Richard B.; Dersch, Christina M.; King, Christine; Kuehne, Martin; Bornmann, William G.; Eshleman, Amy J.; Janowsky, Aaron; Simon, Eric R.; Reith, Maarten E A; Alper, Kenneth.

In: PLoS One, Vol. 8, No. 10, e77262, 16.10.2013.

Research output: Contribution to journalArticle

Antonio, T, Childers, SR, Rothman, RB, Dersch, CM, King, C, Kuehne, M, Bornmann, WG, Eshleman, AJ, Janowsky, A, Simon, ER, Reith, MEA & Alper, K 2013, 'Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation', PLoS One, vol. 8, no. 10, e77262. https://doi.org/10.1371/journal.pone.0077262
Antonio T, Childers SR, Rothman RB, Dersch CM, King C, Kuehne M et al. Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation. PLoS One. 2013 Oct 16;8(10). e77262. https://doi.org/10.1371/journal.pone.0077262
Antonio, Tamara ; Childers, Steven R. ; Rothman, Richard B. ; Dersch, Christina M. ; King, Christine ; Kuehne, Martin ; Bornmann, William G. ; Eshleman, Amy J. ; Janowsky, Aaron ; Simon, Eric R. ; Reith, Maarten E A ; Alper, Kenneth. / Effect of Iboga Alkaloids on μ-Opioid Receptor-Coupled G Protein Activation. In: PLoS One. 2013 ; Vol. 8, No. 10.
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