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

被引:24
作者
Antonio, Tamara [1 ,2 ]
Childers, Steven R. [3 ]
Rothman, Richard B. [4 ]
Dersch, Christina M. [4 ]
King, Christine [1 ,2 ]
Kuehne, Martin [5 ]
Bornmann, William G. [6 ]
Eshleman, Amy J. [7 ,8 ,9 ]
Janowsky, Aaron [7 ,8 ,9 ]
Simon, Eric R. [1 ,2 ]
Reith, Maarten E. A. [1 ,2 ]
Alper, Kenneth [1 ,10 ]
机构
[1] NYU, Sch Med, Dept Psychiat, New York, NY USA
[2] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY USA
[3] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC USA
[4] NIDA, Translat Pharmacol Res Sect, Intramural Res Program, Baltimore, MD USA
[5] Univ Vermont, Dept Chem, Burlington, VT 05405 USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
[7] Oregon Hlth & Sci Univ, Res Serv, VA Med Ctr, Portland, OR 97201 USA
[8] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA
[9] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA
[10] NYU, Dept Neurol, Sch Med, New York, NY 10016 USA
关键词
NALOXONE-PRECIPITATED WITHDRAWAL; NICOTINIC ACETYLCHOLINE-RECEPTOR; INDUCED LOCOMOTOR-ACTIVITY; MORPHINE-WITHDRAWAL; ANTINOCICEPTIVE ACTION; TABERNANTHE-IBOGA; ADENYLYL-CYCLASE; ACUTE SIGNS; NORIBOGAINE; BINDING;
D O I
10.1371/journal.pone.0077262
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu-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-5'-O-(gamma-thio)-triphosphate ([S-35]GTP gamma S) 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 [S-35]GTP gamma S 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 [S-35]GTP gamma S binding in any MOR expressing cells. Noribogaine did not stimulate [S-35]GTP gamma S 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.
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页数:18
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