Deconstructing the Iboga Alkaloid Skeleton


Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound (ACS Publications).

An interesting new scientific paper has been published today. Ibogaine is probably a Neurotrophin (Nerve growth factor) rather than a typical Hallucinogen:

Figure 1. GDNF release and addiction. (A) Glial cell line-derived neurotrophic factor (GDNF) is a small protein that is synthesized and secreted in glial and neuronal cells. It has been shown to protect dopaminergic neurons in the brain and is linked to many brain disorders. Ibogaine, an alkaloid natural product isolated from Tabernanthe iboga, has shown antiaddictive properties, possibly mediated through the induction of GDNF release in the reward circuits of the brain. It was suggested that the GDNF release repairs neuronal circuits altered by the development of the drug dependent state (supported by reduction of alcohol consumption in rodents). (B) Disconnection of the heteroarene and isoquinuclidine systems of the iboga skeleton reveals a novel class of iboga analogs. (C) One such analog, XL-008, is a superior releaser of GDNF in comparison to the iboga alkaloid ibogamine, when tested at a 10 μM concentration after 24 h. Data represent mean ± SD of biological replicates in one experiment from n = 4 independent experiments. One-way ANOVA followed by Dunnett’s Multiple Comparisons Test is shown (**p < 0.01).

Figure 1. GDNF release and addiction. (A) Glial cell line-derived neurotrophic factor (GDNF) is a small protein that is synthesized and secreted in glial and neuronal cells. It has been shown to protect dopaminergic neurons in the brain and is linked to many brain disorders. Ibogaine, an alkaloid natural product isolated from Tabernanthe iboga, has shown antiaddictive properties, possibly mediated through the induction of GDNF release in the reward circuits of the brain. It was suggested that the GDNF release repairs neuronal circuits altered by the development of the drug dependent state (supported by reduction of alcohol consumption in rodents). (B) Disconnection of the heteroarene and isoquinuclidine systems of the iboga skeleton reveals a novel class of iboga analogs. (C) One such analog, XL-008, is a superior releaser of GDNF in comparison to the iboga alkaloid ibogamine, when tested at a 10 μM concentration after 24 h. Data represent mean ± SD of biological replicates in one experiment from n = 4 independent experiments. One-way ANOVA followed by Dunnett’s Multiple Comparisons Test is shown (**p < 0.01).

“Isolated from the West African shrub Tabernanthe iboga, the natural product ibogaine and the other members of the ibogamine alkaloid family have traditionally been used in religious ceremonies, likely due to their dissociative effects observed at high doses.

In recent decades, however, ibogaine has been investigated as an experimental therapeutic for treating substance use disorders (SUDs), with evidence for suppression of craving and self-administration of diverse drugs of abuse in humans (e.g., alcohol, opioids, and3cocaine) for extended periods of time (weeks to months), as well as reduction of acute opioid withdrawal symptoms.4 These clinical findings (mostly uncontrolled clinical studies and anecdotal reports)3 have been recapitulated in animal models.

Unfortunately, despite decades of ongoing interest, ibogaine’s molecular mechanism of action remains undefined. Ibogaine has been reported to bind to, and/or show functional activity at, many central nervous system (CNS) receptors with micromolar potency, including the N-methyl-D-aspartate receptor (NMDAR), the dopamine and serotonin transporters, mu-opioid receptor, sigma 2 receptor, 5-HT2a, acetylcholine receptors, ERG channels, and others,8−11 which, combined with its hallucinogenic effects, makes ibogaine a controversial treatment option.

The complex pharmacology of ibogaine (and its metabolite noribogaine) continues to be studied: while ibogaine has been shown to block NMDA receptors in different brain tissues in the range of 3−10 μM,14−16 it does not appear to activate the mu-opioid receptor, suggesting an indirect mechanism of action for ibogaine’s effects on opioid withdrawal. In addition, the inhibition of human ERG channels by ibogaine at ∼4 μM may account for the heart arrhythmias associated with ibogaine usage.

Therefore, there have been efforts to isolate the key therapeutic mechanism(s) from the dissociative and other potentially dangerous side effects. Most notably, the ibogaine analog 18- methoxycoronaridine (18-MC) was developed in this spirit as an antagonist of α3β4 nicotinic receptor with much improved selectivity for this molecular target over other CNS receptors when compared to ibogaine. 18-MC is effective at reducing self-administration in rodents of several addictive substances, including morphine, cocaine, ethanol, and nicotine, and thus α3β4 nicotinic receptor antagonism is considered an important mechanism of action of ibogaine and 18-MC. However, clinical efficacy of 18-MC has not yet been reported. Others have also developed acyclic ibogaine analogs that show binding to some of the same targets, including dopamine and serotonin transporters, the kappa-opioid receptor, and the NMDA receptor; however, these compounds have apparently not been pursued further.

We were inspired by an intriguing mechanistic hypothesis that links iboga alkaloids to modulation of neurotrophic factor signaling systems. Namely, ibogaine was shown to induce glial cell line-derived neurotrophic factor (GDNF) expression in the ventral tegmental area (VTA) of rats, and it was suggested that GDNF activates an autocrine loop, leading to the increased and long-term synthesis and release of GDNF, which in turn repairs the function of the VTA-ventral striatum reward system (Figure 1A).”

Figure 4. Schematic representation of signaling pathways involved in potentiation of FGF2-induced GDNF release by XL-008. Pharmacological inhibition of XL-008/FGF2 reveals pathway specificity through MAPK and AKT.

Figure 4. Schematic representation of signaling pathways involved in potentiation of FGF2-induced GDNF release by XL-008. Pharmacological inhibition of XL-008/FGF2 reveals pathway specificity through MAPK and AKT.

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