1. Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.
Maisonneuve IM, Glick SD.
Pharmacol Biochem Behav. 2003 Jun;75(3):607-18.
Center for Neuropharmacology and Neuroscience, Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. email@example.com
Abstract: 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity. return to index
2. Metabolism of 18-Methoxycoronaridine, an Ibogaine Analog, to 18-Hydroxycoronaridine by Genetically Variable CYP2C19.
Zhang W, Ramamoorthy Y, Tyndale RF, Glick SD, Maisonneuve IM, Kuehne ME, Sellers EM.
Drug Metab Dispos 2002 Jun 1;30(6):663-669.
Center for Addiction and Mental Health, University of Toronto, Toronto, Canada.
Abstract: 18-Methoxycoronaridine, a newly developed ibogaine analog, has been reported to decrease the self-administration of morphine, cocaine, ethanol, and nicotine. It has also been reported to attenuate naltrexone-precipitated signs of morphine withdrawal. In this study, three metabolites of 18-methoxycoronaridine (18-MC) were separated and identified by high-performance liquid chromatography-electrospray ionization-mass spectrometry-mass spectrometry (HPLC-ESI-MS-MS); the major metabolite was 18-hydroxycoronaridine (18-HC). The other two metabolites were elucidated as hydroxylated metabolites on the basis of their MS-MS spectra. Catalytic studies of 18-MC O-demethylase activity in human liver microsomes indicate that one high affinity enzyme is involved in this reaction (K(m) from 2.81 to 7.9 &mgr;M; V(max) from 0.045 to 0.29 nmol/mg/min). In cDNA-expressing microsomes, only CYP2C19 displayed significant 18-MC O-demethylase activity (K(m) 1.34 &mgr;M; V(max) 0.21 nmol/mg/min). S-Mephenytoin, a selective CYP2C19 inhibitor, inhibited 18-MC O-demethylation by 65% at a concentration of 2 times its K(I), and antibodies against rat 2C (human CYP2C8, 2C9, 2C19) inhibited 18-HC formation by 70%. Studies with other cytochrome P450 (P450)-selective chemical inhibitors and antibodies failed to demonstrate an appreciable role for other P450s in this reaction. In addition, in microsomes from five different human livers, 18-MC O-demethylation correlated with S-mephenytoin 4'hydroxylase activity but not with other P450 probe reactions. These data indicate that 18-HC formation is the predominant pathway of 18-MC metabolism in vitro in human liver microsomes and that this metabolic pathway is primarily catalyzed by the polymorphic CYP2C19. The apparent selectivity of this pathway for CYP2C19 suggests 18-MC as a potentially useful probe of CYP2C19 activity in vitro and in vivo. return to index
3. Antagonism of alpha3beta4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.
Glick SD, Maisonneuve IM, Kitchen BA, Fleck MW.
Eur J Pharmacol 2002 Mar 1;438(1-2):99-105. Center for Neuropharmacology and Neuroscience, Albany Medical College (MC-136), 47 New Scotland Avenue, 12208, Albany, NY, USA
Abstract: The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha3beta4 nicotinic receptors and both agents were more potent at this site than at alpha4beta2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha3beta4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha3beta4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity. return to index
4. Drug discrimination studies with ibogaine.
Helsley S, Rabin RA, Winter JC.
Alkaloids Chem Biol 2001;56:63-77. Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Abstract: The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine? return to index
5. 18-MC reduces methamphetamine and nicotine self-administration in rats.
Glick SD, Maisonneuve IM, Dickinson HA.
Neuroreport 2000 Jun 26;11(9):2013-5. Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA.
Abstract: In previous studies, 18-methoxycoronaridine (18-MC), a novel iboga alkaloid congener, has been found to decrease the intravenous self-administration of morphine and cocaine in rats. In the present study, 18-MC (1-40 mg/kg, i.p.) dose-dependently decreased the i.v. self-administration of methamphetamine and nicotine. As in the previous studies, drug self-administration was reduced for > or = 24 h after the highest dose of 18-MC. A comparison of 18-MC's interactions with all four drugs of abuse studied so far indicated that 18-MC is least effective in decreasing methamphetamine self-administration and most potent in decreasing nicotine self-administration. The results suggest that a nicotinic antagonist action of 18-MC contributes to its putative anti-addictive efficacy. return to index
6. Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig.
Mundey MK, Blaylock NA, Mason R, Glick SD, Maisonneuve IM, Wilson VG.
Br J Pharmacol 2000 Apr;129(8):1561-8. School of Biomedical Sciences, The Medical School, E. Floor, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH.
Abstract:Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to possess antiaddictive properties in several models of drug dependence. We have examined their effect at mu-opioid receptors regulating neurogenic contractions of several smooth muscle preparations and also against spontaneous contractions of the rat isolated portal vein. Ibogaine (pIC(50) 5.28) and 18-methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of cholinergic contractions of the guinea-pig ileum which was not affected by the opioid receptor antagonist naloxone (1 microM). In the rat isolated vas deferens ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement of purinergic contractions. Both agents (30 microM) caused a 3 - 5 fold rightward displacement of DAMGO-induced inhibition of purinergic contractions, but similar effects were observed for ibogaine against alpha(2)-adrenoceptor-mediated inhibition of neurogenic responses. In the guinea-pig isolated bladder both ibogaine (10 microM) and 18-methoxycoronaridine (10 microM) caused a 2 fold increase in the purinergic component of neurogenic contractions without significantly altering cholinergic contractions or responses to exogenous ATP. In contrast, ibogaine (1 - 30 microM), but not 18-methoxycoronaridine, caused a concentration-dependent enhancement of spontaneous contractions of the rat isolated portal vein. In summary, while ibogaine and 18-methoxycoronaridine modulated electrically-evoked contractions in the three preparations examined, we have no evidence for a selective interaction with pre-junctional mu-opioid receptors. The pronounced enhancement of purinergic contractions produced by both agents is a novel finding and worthy of further investigation. return to index
7. Synthesis of enantiomerically pure (+)- and (-)-18-methoxycoronaridine hydrochloride and their preliminary assessment as anti-addictive agents.
King CH, Meckler H, Herr RJ, Trova MP, Glick SD, Maisonneuve IM.
Bioorg Med Chem Lett 2000 Mar 6;10(5):473-6. Albany Molecular Research, Inc., NY 12203, USA.
Abstract: Chemical resolution of racemic 18-methoxycoronaridine (18-MC) was achieved by the formation of its diastereomeric sulfonamides with either (R)-(-)- or (S)-(+)-camphorsulfonyl chloride. Preliminary assessment of (+)-, (-)-, and (+/-)-18-MC x HCl showed similar effects on morphine self-administration in a rat model, and similar affinities at the kappa opioid receptors. return to index
8. 18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action.
Glick SD, Maisonneuve IM, Szumlinski KK.
Ann N Y Acad Sci 2000;914:369-86. Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. firstname.lastname@example.org
Abstract: 18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine. return to index
9. Development of novel medications for drug addiction. The legacy of an African shrub.
Glick SD, Maisonneuve IM.
Ann N Y Acad Sci 2000;909:88-103. Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. email@example.com
Abstract: Ibogaine, one of several alkaloids found in the root bark of the African shrub Tabernanthe iboga, has been claimed to be effective in treating multiple forms of drug abuse. Problems associated with side effects of ibogaine have spawned a search for more effective and safer structural derivatives. 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, appears to have substantial potential for broad use as an anti-addictive therapy. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a non-drug reinforcer (water). Ibogaine and 18-MC appear to reduce the reinforcing efficacies, rather than the potencies, of drugs of abuse. Both ibogaine and 18-MC decreases extracellular levels of dopamine in the nucleus accumbens while only ibogaine increases serotonin levels in this brain region. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the accumbens; only ibogaine enhances cocaine-induced increases in dopamine levels. Ibogaine produces whole body tremors and, at high doses (at least 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, causes bradycardia at high doses. Ibogaine and its metabolite noribogaine have low microM affinities for kappa and mu opioid receptors, NMDA receptors, 5HT-3 receptors, sigma-2 sites, sodium channels and the serotonin transporter. 18-MC has low microM affinities at all three opioid receptors and at 5HT-3 receptors but much lower or no affinities for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. 18-MC also has (+) and (-) enantiomers, both of which are active. Considered together, all of the data indicate that 18-MC should be safer than ibogaine and at least as efficacious as an anti-addictive medication. return to index
10. Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats.
Wei D, Maisonneuve IM, Kuehne ME, Glick SD.
Brain Res 1998 Aug 3;800(2):260-8. Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY 12208, USA.
Abstract: The iboga alkaloid, ibogaine, its metabolite, noribogaine, and the congener, 18-methoxycoronaridine (18-MC) have all been claimed to have anti-addictive properties in animal models, but the mechanisms underlying these effects are unclear. Ibogaine and noribogaine were shown to have affinity for the serotonin transporter, and inhibition of serotonin reuptake has been proposed to be involved in their anti-addictive actions. It is not known yet if 18-MC also has this property. In vivo microdialysis and HPLC (microbore) were used to determine acute changes in extracellular serotonin levels in nucleus accumbens (NAC) and striatum (STR) after both i.p. (40 mg/kg for all drugs) and i.v. (1-10 mg/kg for ibogaine and noribogaine) drug administration in awake freely moving female Sprague-Dawley rats (250-275 g). After i.p. administration, ibogaine, noribogaine and 18-MC had very different effects on extracellular serotonin levels in both NAC and STR: ibogaine elicited large increases (up to 25-fold in NAC and 10- fold in STR), noribogaine produced moderate increases (up to 8-fold in NAC and 5-fold in STR), and 18-MC had no effect in either brain region. These and other data suggest that (1) the serotonergic system may not be an essential factor in the anti-addictive actions of these drugs; (2) ibogaine (or an unidentified metabolite) may release serotonin as well as inhibit its reuptake; (3) stimulation of the ascending serotonergic system may mediate ibogaine's hallucinogenic effect; and (4) 18-MC probably has no affinity for the serotonin transporter, and is unlikely to be a hallucinogen. Copyright 1998 Elsevier Science B.V. All rights reserved. return to index
11. Effects of 18-methoxycoronaridine on acute signs of morphine withdrawal in rats.
Rho B, Glick SD.
Neuroreport 1998 May 11;9(7):1283-5. Department of Pharmacology and Neuroscience (A-136), Albany Medical College, NY 12208, USA.
Abstract: Ibogaine, an alkaloid found in the root bark of the African shrub Tabernanthe iboga, has been claimed to interrupt opioid dependence in humans; in animals, it has been shown to inhibit morphine self-administration and to attenuate signs of morphine withdrawal. However, ibogaine has some neurotoxicity, and because of this, efficacious and safer congeners of ibogaine have been sought, 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, has been shown, in animals, to mimic the effects of ibogaine on morphine self-administration without producing any ibogaine-like neurotoxiticity. In the present study, 18-MC was shown to attenuate five of seven signs of morphine withdrawal in rats. The data suggest that 18-MC will ameliorate symptoms of opioid dependence in humans. return to index
12. Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats.
Rezvani AH, Overstreet DH, Yang Y, Maisonneuve IM, Bandarage UK, Kuehne ME, Glick SD.
Pharmacol Biochem Behav 1997 Oct;58(2):615-619.
Abstract: We previously reported that single administration of ibogaine, an indol alkaloid with antiaddictive properties, dose dependently reduced alcohol intake in
three strains of alcohol-preferring rats. The present study examined the effect of different doses of a newly developed nontoxic ibogaine analogue,
18-methoxycoronaridine (18-MC), on alcohol intake. Selectively bred alcohol-preferring rats received a single intraperitoneal injection of vehicle or 5, 20
and 40 mg/kg of 18-MC at 9:30 AM, and their consumption of alcohol, water and food was measured for 24 h. Our results demonstrate that a single injection
of 18-MC significantly and dose dependently attenuated alcohol consumption and preference and commensurately increased water intake. Only the highest
dose of 18-MC significantly decreased food intake. Although the true mechanism of action of 18-MC in suppressing alcohol intake is not yet fully understood,
it may, like ibogaine, exert its attenuating effects on alcohol consumption by modulating neurotransmitters believed to be involved in the regulation of alcohol
intake. return to index
13. Time-dependent interactions between iboga agents and cocaine.
Maisonneuve IM, Visker KE, Mann GL, Bandarage UK, Kuehne ME, Glick SD.
Eur J Pharmacol 1997 Oct 8;336(2-3):123-126.
Abstract: The purpose of this study was to clarify the effects of iboga agents on cocaine-induced hyperactivity. Both inhibition and enhancement of cocaine-induced
activity by ibogaine have been reported. In the present study, rats were treated with either ibogaine (40 mg/kg, i.p.), noribogaine (40 mg/kg, i.p.),
18-methoxycoronaridine (40 mg/kg, i.p.), or saline, 1 or 19 h prior to the administration of cocaine (20 mg/kg, i.p.) or saline. Motor activity was monitored
thereafter for 3 h. All three iboga agents had acute inhibitory effects and delayed potentiating effects on cocaine-induced hyperactivity. These time-dependent
effects, which could not be attributed to the motor activity induced by the iboga agents alone, account for divergent results reported in the literature. return to index
14. 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine
self-administration and on mesolimbic dopamine release in rats.
Glick SD, Kuehne ME, Maisonneuve IM, Bandarage UK, Molinari HH.
Brain Res 1996 May 6;719(1-2):29-35.
Abstract: Ibogaine, a naturally occurring iboga alkaloid, has been claimed to be effective in treating addiction to opioids and stimulants, and has been reported to
inhibit morphine and cocaine self-administration in rats. However, ibogaine also has acute nonspecific side effects (e.g. tremors, decreased motivated
behavior in general) as well as neurotoxic effects (Purkinje cell loss) manifested in the vermis of the cerebellum. 18-Methoxycoronaridine (MC) is a novel,
synthetic iboga alkaloid congener that mimics ibogaine's effects on drug self-administration without appearing to have ibogaine's other adverse effects.
Acutely, in rats, MC decreased morphine and cocaine self-administration but did not affect bar-press responding for water. In some rats, treatment with MC
(40 mg/kg) induced prolonged decreases in morphine or cocaine intake lasting several days or weeks. MC had no apparent tremorigenic effect, and there was
no evidence of cerebellar toxicity after a high dose (100 mg/kg) of MC. Similar to the effects of ibogaine and other iboga alkaloids that inhibit drug
self-administration, MC (40 mg/kg) decreased extracellular levels of dopamine in the nucleus accumbens. MC therefore appears to be a safer, ibogaine-like
agent that might be useful in the treatment of addictive disorders. return to index
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