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18-methoxycoronaridine

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  • 1. 18-methoxycoronaridine dr shabeel pn
  • 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 A 3 B 4 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.