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]
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.
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).
^Patel, M. B.; Miet, C.; Poisson, J. (1967). "Alkaloids of some African Tabernaemontana". Annales Pharmaceutiques Françaises. 25 (5): 379–384.
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abMair CE, de Miranda Silva C, Grienke U, Kratz JM, Carreño F, Zimmermann ES, de Araújo BV, Dalla Costa T, Rollinger JM (July 2016). "Pharmacokinetics of hERG Channel Blocking Voacangine in Wistar Rats Applying a Validated LC-ESI-MS/MS Method". Planta Medica. 82 (11–12): 1030–8.
doi:
10.1055/s-0042-107800.
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^Terada Y, Horie S, Takayama H, Uchida K, Tominaga M, Watanabe T (February 2014). "Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree". Journal of Natural Products. 77 (2): 285–97.
doi:
10.1021/np400885u.
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