Voacangine

Pharmacology

Pharmacodynamics

Voacangine exhibits AChE inhibitory activity. Docking simulation reveals that it has inhibitory effect on VEGF2 kinase and reduces angiogenesis. Like ibogaine, its a potent HERG blocker in vitro. It also acts as antagonist to TRPM8 and TRPV1 receptor, but agonist of TRPA1.

Pharmacokinetics

The absolute bioavailability of voacangine is around 11–13%.

Side effects

High doses of voacangine produce convulsions and asphyxia.

Chemistry

Biosynthesis

The late-stage biosynthesis of (-)-voacangine in Tabernanthe iboga, a (-)-ibogamine-type alkaloid, has been elucidated via homology-guided transcriptome mining. Suspected RNA transcripts involved in (-)-voacangine biosynthesis were identified via sequence homology to previously described enzymes comprising the (+)-catharanthine biosynthesis, a (+)-ibogamine-type alkaloid from the taxonomically related plant Catharanthus roseus.

Ibogamine-type alkaloids are biosynthesized from the late stage intermediate stemmadenine acetate, a strictosidine-derived biosynthetic intermediate for a wide number of plant natural products. The biosynthesis of stemmadenine acetate has been characterized in C. roseus but remains uncharacterized in T. iboga.

Conversion of stemmadenine acetate to (-)-voacangine in T. iboga involves five enzymes. First, stemmadenine acetate (1) is converted to precondylocarpine acetate (2) by one of three T. iboga precondylocarpine acetate synthases (TiPAS1/2/3), a flavin-dependent oxidase. Next, 2 is reduced to the enamine (3), dihydroprecondylocarpine acetate, by one of two NADPH-dependent T. iboga dihydroprecondylocarpine acetate synthase (TiDPAS1/2).

Up to this point, the biosynthetic path towards the (-)-ibogamine alkaloids and (+)-ibogamine alkaloids is identical. Stereochemical divergence occurs during the cyclization step, whereby T. iboga coronaridine synthase (TiCorS), a catharanthine synthase (CS) homologue, catalyzes a stereoselective formal Diels-Alder reaction on dehydrosecodine (4) to form coronaridine iminium (5). A proposed mechanism for dehydrosecodine formation from 3 involves iminium-formation/deacetylation, enamine-formation, and subsequent isomerization. Reduction of 5 to (-)-coronaridine (6) is proposed to be catalyzed by TiDPAS, although it is unclear if the reduction is actually enzymatic due to a lack of a reaction trial with only NADPH. After formation of 6, the substrate is then 10-hydroxylated by ibogamine 10-hydroxylase (I10H), a CYP450 enzyme, and subsequently 10-O-methylated by noribogaine-10-O-methyltransferase (N10OMT), a SAM dependent enzyme, to form (-)-voacangine (7).

Notes

References

References

1. "Compound Report Card CHEMBL182120 - Voacangine". ChEMBL.
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5. (2002). "Extraction Studies of ''Tabernanthe iboga'' and ''Voacanga africana''". Natural Product Letters.
6. "Derivatives of the Ibogaine Alkaloids".
7. Tsing Hua. (January 28, 2006). "Antiaddictive Indole Alkaloids in ''Ervatamia yunnanensis'' and their Bioactivity". Academic Journal of Second Military Medical University.
8. (December 2023). "Unknown}}{{dead link".
9. (2008). "Two fast screening methods (GC-MS and TLC-ChEI assay) for rapid evaluation of potential anticholinesterasic indole alkaloids in complex mixtures". Annals of the Brazilian Academy of Sciences.
10. (June 2005). "Indole alkaloids from Tabernaemontana australis (Muell. Arg) Miers that inhibit acetylcholinesterase enzyme". [[Bioorganic & Medicinal Chemistry]].
11. (March 2020). "Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI". [[Biomolecules]].
12. (January 2012). "A natural small molecule voacangine inhibits angiogenesis both in vitro and in vivo". [[Biochemical and Biophysical Research Communications]].
13. (January 28, 2006). "Antiaddictive Indole Alkaloids in ''Ervatamia yunnanensis'' and their Bioactivity". Academic Journal of Second Military Medical University.
14. (July 2016). "Pharmacokinetics of hERG Channel Blocking Voacangine in Wistar Rats Applying a Validated LC-ESI-MS/MS Method". [[Planta Medica]].
15. (February 2014). "Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree". [[Journal of Natural Products]].
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18. (31 July 2019). "Biosynthesis of an Anti-Addiction Agent from the Iboga Plant". Journal of the American Chemical Society.
19. (March 6, 2018). "Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine". Proceedings of the National Academy of Sciences.
20. (September 7, 2018). "Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga". J Biol Chem.
21. See supplementary figure 15 of the Farrow et al. paper, citation 18. After initial incubation with TiCorS, no trial was run with just NADPH.