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18-methoxycoronaridine A review by Jonathan Freedlander, BA

18-methoxycoronaridine A review by Jonathan Freedlander, BA. Introduction. Synthetic iboga alkaloid congener Developed by team at Albany Medical College Primary investigator: Stanley Glick Similar anti-addictive effects as ibogaine seen in animal research Non-tremerogenic and non-neurotoxic

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18-methoxycoronaridine A review by Jonathan Freedlander, BA

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  1. 18-methoxycoronaridineA review byJonathan Freedlander, BA

  2. Introduction • Synthetic iboga alkaloid congener • Developed by team at Albany Medical College • Primary investigator: Stanley Glick • Similar anti-addictive effects as ibogaine seen in animal research • Non-tremerogenic and non-neurotoxic • May not be a psychedelic

  3. Effects • No evidence of tremorogenic activity • Does not decrease heart rate, ibogaine can • No evidence of neurotoxicity at doses up to 300 mg/kg • Glick et al hypothesize that ibogaine’s putative neurotoxicity at high doses is due to its overstimulation of the olivio-cerebellar pathway, damaging Purkinje cells • Attenuates self-administration of cocaine, morphine, alcohol, methamphetamine, and nicotine in rats

  4. Attenuates of symptoms of morphine withdrawal (teeth chattering, wet-dog shakes, and diarrhea) • Does not affect grooming behavior • Ibogaine decreases grooming behaviour (grooming behavior is another sign of morphine withdrawal in rats) • Does decrease burying behavior (another withdrawal symptom) • Ibogaine does not decrease burying behavior

  5. Least effective on methamphetamine, most effective on nicotine • Longer lasting reduction of morphine self administration than ibogaine • Approximately twice as potent in attenuation of oral nicotine self-administration as ibogaine • Attenuation of morphine and cocaine self- administration lasted at least a day, and up to two weeks after repeated administration

  6. Some rats responded to treatment (for morphine and cocaine) after one dose, some after two or doses, and a few did not respond at all • 18-MC pretreatment enhances morphine induced locomotor activation in acute morphine treat rats, but blocks locomotor sensitization in rats having been repeatedly administered morphine • Ibogaine reduces morphine induced locomotion in acute morphine treated rats

  7. Does not affect responding for a nondrug reinforcer (water) • Ibogaine has been shown to decrease responding for water • Like ibogaine, attenuates and then increases cocaine and methamphetamine induced locomotion and stereotypy • Like ibogaine, reduces methamphetamine induced behavioral disinhibition and novelty seeking • As measured by # of entries into the open arm of a maze

  8. Pharmacology • Primary mechanism of action thought to be decrease of extracellular dopamine and the DA metabolite dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAC) • Does not affect level of DA metabolite homovanillic acid (HVA) in the NAC • Attenuates nicotine, morphine, and cocaine induced dopamine release • May affect cocaine induced locomotion via action at some sites downstream of the midbrain dopamine neurons

  9. Does not affect basal dopamine,HVA, or DOPAC • Lack of effect on HVA shows that it may exert its dopaminergic effects by interfering with DA release mechanisms, without affecting DA synthesis • Unlike ibogaine, does not cause an increase in extracellular serotonin in the nucleus accumbens • This is why it is hypothesized that 18-MC may not be psychedelic

  10. Like ibogaine, acts as an antagonist at 34 nicotinic receptors • Similar affinity for kappa opioid receptors as ibogaine • Significantly lower affinity for delta opioid receptors than ibogaine • This is presumed to be the reason for the difference in effects on morphine induced locomotion

  11. Has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter • Like ibogaine, is sequestered in fat • Metabolism catalyzed by CYP2C19 • Primary metabolite: 18-hydroxycoronaridine (18-HC)

  12. Limitations • Has only been tested on laboratory animals • Has only been administered intraperitonally • Studies have been conducted by a small set of researchers • May not be psychedelic - this could conceivably be a limitation, as the visualizations caused by ibogaine seem to play a significant role in its therapeutic actions in humans

  13. References • Glick, S. D., Kuehne, M. E, Maisonneuve, I. M., Bandarage, U. K., and Molinari, H. H. (1995). 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administrtion and on mesolimbic dopamine release in rats. Brain Research, Vol. 719, 29 -35. • Glick, S. D., Maisonneuve, I. M., and Dickinson, H. A. (2000). 18-MC reduces methamphetamine and nicotine self-administration in rats. NeuroReport, Vol. 11, 2013 - 2015. • Glick, S. D., Maisonneuve, I. M., and Dickinson, H. A. (2000). 18-Methoxycoronaridine attenuates nicotine-induced dopamine release and nicotine preferences in rats. Psychopharmacology, Vol. 139, 274 - 280. • Glick, S., D., Maisonneuve, I. M., Kitchen, B. A., Fleck, M. W. (2002). Antagonism of A3B4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. European Journal of Pharmacology, Vol 438., 99-105. • Maisonneuve, I. M., Visker, K. E., Mann G. L., Bandarage, U. K., Kuehne, M. E, Glick, S. D. (1997). Time- dependent interactions between iboga agents and cocaine. European Journal of Pharmacology, Vol. 336, 123 - 126. • Mundey, M. K., Blaylock, N. A. , Mason, R., Glick, S. D., Maisonneuve, I. M., and Wilson, V. G. (2000). Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig. British Journal of Pharmacology, Vol. 129, 1561 - 1568.

  14. Popik, P and Skolnik, P. (1999) The Alkaloids, Chapter 3, Vol. 52, Academic Press, San Diego, CA, 197 - 231. • Rezvani, A. H., Overstreet, D. H., Yang, Y., Maisonnevue, I. M., Bandarage, U. K., Kuehne, M. E., and Glick, S. D. (1999). Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats. Pharmacology, Biochemistry, and Behavior, Vol. 58, 615 - 619. • Rho, B. and Glick, S. D. (1998). Effects of 18-methoxycoronaridine on acute signs of morphine withdrawal in rats. NeuroReport Vol. 9, 1283 - 1285. • Szumlinski, K. K., Balogun, M. Y., Maisonneuve, I. M., and Glick S. D. (2000). Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats. Psychopharmacology, Vol. 151, 234 - 241. • Szumlinski, K. K., Maisonneuve, I. M., and Glick, S. D. (2000). Iboga interaction with psychomotor stimluants: panacea in the paradox? Toxicon, Vol. 39, 75 - 86. • Szumlinski, K. K., Maisonneuve, I. M., and Glick, S. D. (2000). The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopaamine responses produced by repeated morphine treatment. Brain Researh, Vol. 864, 13 - 23. • Szumlinski, K. K., McCafferty, C. A., Maisonneuve, I. M., and Glick, S. D. (2000). Interactrions between 18-methoxycoronaridine (18-MC) and cocaine: dissociation of behavioral and neurochemical sensitization. Brain Research, Vol. 871, 245 - 258.

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