1 / 14

Review of 18-Methoxycoronaridine: Effects and Pharmacology

This review explores the synthetic iboga alkaloid congener, 18-MC, developed by the team at Albany Medical College. It showcases its potential as a non-tremorogenic and non-neurotoxic substance with anti-addictive effects similar to ibogaine, focusing on its pharmacological mechanisms and limitations based on animal research.

margolis
Download Presentation

Review of 18-Methoxycoronaridine: Effects and Pharmacology

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related