Voacangine

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Voacangine
Stereo structural formula of voacangine
Ball-and-stick model of the voacangine molecule
Names
IUPAC name
12-Methoxyibogamine-18-carboxylic acid, methyl ester
Systematic IUPAC name
Methyl 17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18] nonadeca-2(10),4,6,8-tetraene-1-carboxylate[1]
Other names
Methyl 12-methoxyibogamine-18-carboxylate
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.214.137 Edit this at Wikidata
MeSH Voacangine
UNII
  • InChI=1S/C22H28N2O3/c1-4-14-9-13-11-22(21(25)27-3)19-16(7-8-24(12-13)20(14)22)17-10-15(26-2)5-6-18(17)23-19/h5-6,10,13-14,20,23H,4,7-9,11-12H2,1-3H3/t13-,14+,20+,22-/m1/s1 ☒N
    Key: MMAYTCMMKJYIAM-PHKAQXKASA-N ☒N
  • O=C(OC)[C@@]43c2[nH]c1ccc(OC)cc1c2CCN5[C@H]3[C@H](C[C@H](C4)C5)CC
Properties
C22H28N2O3
Molar mass 368.477 g·mol−1
Melting point 136 to 137 °C (277 to 279 °F; 409 to 410 K)
log P 3.748
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Voacangine (12-methoxyibogamine-18-carboxylic acid methyl ester) is an

barbiturates.[8] Under UV-A and UV-B light its crystals fluoresce blue-green, and it is soluble in ethanol
.

Pharmacology

Pharmacodynamics

Voacangine exhibits AChE inhibitory activity.[9][10] Docking simulation reveals that it has inhibitory effect on VEGF2 kinase[11] and reduces angiogenesis.[12][13] Like ibogaine, its a potent HERG blocker in vitro.[14] It also acts as antagonist to TRPM8 and TRPV1 receptor, but agonist of TRPA1.[15][16]

Pharmacokinetics

The absolute bioavailability of voacangine is around 11–13%.[14]

Side effects

High doses of voacangine produce convulsions and asphyxia.[17]

Chemistry

Biosynthesis

The late-stage biosynthesis of (-)-voacangine in Tabernanthe iboga, a (-)-ibogamine-type alkaloid, has been elucidated via homology-guided transcriptome mining.[18] Suspected RNA transcripts involved in (-)-voacangine biosynthesis were identified via sequence homology to previously described enzymes comprising the (+)-catharanthine biosynthesis,[19] 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[19] but remains uncharacterized in T. iboga.

Schematic of the late-stage biosynthesis of (-)-voacangine in Tabernanthe 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.[Note 1] 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,[20]
to form (-)-voacangine (7).

See also

Notes

  1. ^ See supplementary figure 15 of the Farrow et al. paper, citation 18. After initial incubation with TiCorS, no trial was run with just NADPH.

References

  1. ^ "Compound Report Card CHEMBL182120 - Voacangine". ChEMBL.
  2. PMID 5611538
    .
  3. S2CID 910492
    .
  4. S2CID 84629414
    .
  5. S2CID 23390825
    .
  6. ^ US patent 2813873, "Derivatives of the Ibogaine Alkaloids", issued 1957-11-19 
  7. ^ Tsing Hua (January 28, 2006). "Antiaddictive Indole Alkaloids in Ervatamia yunnanensis and their Bioactivity". Academic Journal of Second Military Medical University. Archived from the original on February 13, 2012. Retrieved August 9, 2008.
  8. ^ "Unknown" (PDF).[permanent dead link]
  9. PMID 18797794. Archived from the original
    (PDF) on 2020-02-19.
  10. PMID 15911323
    .
  11. PMID 32230857
    .
  12. PMID 22155252
    .
  13. ^ "Antiaddictive Indole Alkaloids in Ervatamia yunnanensis and their Bioactivity". Academic Journal of Second Military Medical University. January 28, 2006.
  14. ^
    S2CID 24504763
    .
  15. PMID 24484240
    .
  16. S2CID 25706616
    .
  17. ^ "Erowid Voacanga africana Vault : Info #1".
  18. PMID 31364847
    .
  19. ^
    PMID 29511102
    .
  20. PMID 30030374
    .
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