Metabolism of 18-Methoxycoronaridine, an Ibogaine Analog, to 18-Hydroxycoronaridine by Genetically Variable CYP2C19

Zhang, Wenjiang; Ramamoorthy, Yamini; Tyndale, Rachel F.; Glick, Stanley D.; Maisonneuve, Isabelle M.; Kuehne, Martin E.; Sellers, Edward M.

doi:10.1124/dmd.30.6.663

Cited by 18 publications

(19 citation statements)

References 29 publications

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“…In addition to our previous results in Torpedo AChRs (Arias et al, 2011), this is the first time that the inhibitory potency for (+)-catharanthine, the scaffold structure for the coronaridine congener series, is obtained in the h␣3␤4 AChR. Although previous results indicate that (±)-18-HC inhibits rat ␣3␤4 AChRs (Pace et al, 2004), this is the first time that quantitative values are obtained for (±)-18-HC, the most important metabolite of 18-MC (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 78%

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Arias

Targowska-Duda

Feuerbach

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Section: Discussionmentioning

confidence: 78%

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Arias

Targowska-Duda

Feuerbach

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…In this regard, 18-MC is rapidly metabolized (i.e., half-life ∼100 min) to 18-HC (Zhang et al, 2002; Maissonneuve and Glick, 2003), which also has higher selectivity for hα3β4 AChRs (this paper), suggesting a potential role in the behavioral effects mediated by 18-MC. However, only small amounts of this metabolite were found in tissues, indicating that it may account for only a minimal activity (Maissonneuve and Glick, 2003).…”

Section: Discussionmentioning

confidence: 79%

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

Arias

Jin

Feuerbach

et al. 2017

The International Journal of Biochemistry & Cell Biology

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The inhibitory activity of coronaridine congeners on human (h) α4β2 and α7 nicotinic acetylcholine receptors (AChRs) is determined by Ca2+ influx assays, whereas their effects on neurons in the ventral inferior (VI) aspect of the mouse medial habenula (MHb) are determined by patch-clamp recordings. The Ca2+ influx results clearly establish that coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to hα4β2 and hα7 subtypes, and with the following potency sequence, for hα4β2: (±)-18-methoxycoronaridine [(±)-18-MC] > (+)-catharanthine > (±)-18-methylaminocoronaridine [(±)-18-MAC] ∼ (±)-18-hydroxycoronaridine [(±)-18-HC]; and for hα7: (+)-catharanthine > (±)-18-MC > (±)-18-HC > (±)-18-MAC. Interestingly, the inhibitory potency of (+)-catharanthine (27 ± 4 μM) and (±)-18-MC (28 ± 6 μM) on MHb (VI) neurons was lower than that observed on hα3β4 AChRs, suggesting that these compounds inhibit a variety of endogenous α3β4* AChRs. In addition, the interaction of bupropion with (−)-ibogaine sites on hα3β4 AChRs is tested by [3H]ibogaine competition binding experiments. The results indicate that bupropion binds to ibogaine sites at desensitized hα3β4 AChRs with 2-fold higher affinity than at resting receptors, suggesting that these compounds share the same binding sites. In conclusion, coronaridine congeners inhibit hα3β4 AChRs with higher selectivity compared to other AChRs, by interacting with the bupropion (luminal) site. Coronaridine congeners also inhibit α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets for their anti-addictive activities.

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“…The apparent long-lasting effects of the two treatments (see Figs. 3a and 4a) during the recovery session could possibly be due to an effect of 18-hydroxycoronaridine, an active metabolite present in plasma in low concentrations (Glick et al 1999; Zhang et al 2002). …”

Section: Discussionmentioning

confidence: 99%

18-Methoxycoronaridine: a potential new treatment for obesity in rats?

et al. 2008

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Rationale Excessive eating often leads to obesity. Although a variety of neurotransmitters and brain regions are involved in modulating food intake, a role of accumbal dopamine is thought to be critical for several aspects of this behavior. Since 18-methoxycoronaridine (18-MC), a selective antagonist of α3β4 nicotinic receptors, was previously shown to alter dopamine release in the nucleus accumbens in response to chronic injections of cocaine and morphine, this drug could be a promising therapy for abnormal eating behavior. Objectives Assess the effect of 18-MC on the consumption of sucrose (15%) vs. water in a self-administration paradigm and on the intake of freely available palatable fluids (i.e., 5% sucrose, 0.1% saccharin, and 0.6% saline solutions) as well as on water intake. Determine whether repeated administration of 18-MC (20 mg/kg i.p.) affects weight gain, food intake, and fat deposition in rats drinking 30% sucrose solution. Results Acute administration of 18-MC (10–40 mg/kg i.p.) reduced operant responding for sucrose and decreased ad libitum ingestion of sucrose, saccharin, and saline. The highest dose of 18-MC also reduced consumption of water when palatable fluids were not available. In rats having unlimited access to sucrose (30%), chronic treatment with 18-MC (20 mg/kg i.p.) prevented sucrose-induced increases in body weight, decreased fat deposition, and reduced consumption of sucrose while not altering food intake. Conclusions These data suggest that antagonism of α3β4 nicotinic receptors may be involved in the regulation of intake of palatable substances regardless of its caloric value and may participate in maintaining obesity.

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Metabolism of 18-Methoxycoronaridine, an Ibogaine Analog, to 18-Hydroxycoronaridine by Genetically Variable CYP2C19

Cited by 18 publications

References 29 publications

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

Selectivity of coronaridine congeners at nicotinic acetylcholine receptors and inhibitory activity on mouse medial habenula

18-Methoxycoronaridine: a potential new treatment for obesity in rats?

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