The iboga alkaloids

The paper defines "iboga alkaloids" at four overlapping levels: alkaloids isolated from Tabernanthe iboga; psychoactive alkaloids used in Central African ceremonial contexts; a chemical definition based on an indole nucleus fused to an isoquinuclidine system; and a biogenetic definition tied to specific rearrangements of secologanoside-derived carbons. Lotsof and colleagues adopt a biogenetic nomenclature for the review and restrict coverage to alkaloids built on the ibogan, isoplumeran and isoeburnan skeletons. The authors note that only a small subset of Apocynaceae genera produce these alkaloids and that, among roughly 100 known iboga-type compounds, catharanthine and ibogaine have driven the most chemical and biological interest, the latter for its putative anti‑addiction properties. This chapter aims to update chemical, biosynthetic, structural, synthetic and biological knowledge of iboga alkaloids from literature published roughly between 2000 and 2016. In doing so, the authors emphasise unresolved questions in biosynthesis, challenges in absolute configuration determination and the continued discovery of new monomeric and dimeric iboga derivatives, while signalling the medicinal interest in ibogaine and synthetic analogues such as 18‑OMe‑coronaridine (18‑MC).

The extracted text does not present a formal methods section because the work is a narrative, topical review rather than an original experimental study. The authors surveyed published literature spanning about 2000–2016, chose a biogenetic nomenclature for clarity, and organised the chapter into thematic sections covering biosynthesis, structural elucidation and reactivity, newly reported molecules (monomers and dimers), synthetic approaches, analytical methods, pharmacology and toxicology, and biological screening results. Where appropriate, the authors draw on structural determinations reported in the primary literature (NMR, NOE, coupling constants, ECD, Mosher derivatives, and X‑ray crystallography including anomalous scattering for absolute configuration). They discuss biosynthetic proposals based on classical tracer work and mechanistic hypotheses (for example, Diels–Alder‑like formations and possible enzymatic catalysis), and they integrate spectroscopic evidence and, when available, chemical correlations or total synthesis that have been used to confirm structures. For biological and pharmacological topics the review summarises receptor and activity profiling, metabolite identification, forensic/analytical methods (notably LC–MS with electrospray ionisation), and a range of in vitro screening assays that were reported for new isolates.

Biosynthesis and chemistry: The authors report that detailed modern biosynthetic data for catharanthine and coronaridine remain limited; most mechanistic inferences still rest on tracer studies from the 1970s. Preakuammicine and stemmadenine remain central intermediates in proposed pathways, while the highly labile dehydrosecodine has not been detected. Formation of the azabicyclic (isoquinuclidine) ring is postulated to involve a Diels–Alder‑like step, and the possibility of an enzyme‑mediated Diels–Alderase is noted as an area of interest because such enzymes are rare. Structural elucidation: Advances in high‑field NMR, combined with NOE experiments, coupling constants, Mosher derivatisation, ECD (including ab initio calculations and the exciton chirality rule) and X‑ray crystallography, have improved assignments for many recent isolates. Nonetheless, absolute configuration remains unresolved for numerous compounds; the authors highlight four principal approaches (NMR/Mosher, circular dichroism/computational ECD, X‑ray with anomalous scattering, and total/partial synthesis) and note that extraction artefacts and mass spectrometric misbehaviour (e.g. [M‑2] fragments) complicate structural work. New natural products: The review documents continued discovery of new iboga‑type alkaloids, reporting about 100 compounds overall. Many new monomers are closely related to ibogamine or coronaridine, differing by oxidation at C‑19, C‑10/C‑11 of the indole, or in the isoquinuclidine fragment. Examples include several 19‑hydroxy and 19‑keto derivatives, hydroxy‑indolenines, and numerous 3‑substituted derivatives that may sometimes reflect extraction artefacts. Structural rearrangements (seco derivatives and ring‑contracted variants) and rare skeletons (isoplumeran, isoeburnan) are described, with several structures secured by X‑ray analysis. Dimers: The authors report 49 newly described dimeric (bisindole) alkaloids since the prior review, adding to roughly 40 earlier bisindoles. Most dimers combine a conserved vobasinyl residue with a diverse iboga moiety, and linkages commonly occur at C‑3'. Structural elucidation of dimers relies on HR‑MS and comprehensive 2D NMR, with NOE and HMBC correlations used to assign connectivity and relative stereochemistry; only a minority have had absolute configurations determined. Synthesis: Total synthesis remains of academic interest rather than routine practice for structure proof, since many target compounds remain available from natural sources. The review summarises several modern synthetic strategies: biosynthesis‑inspired routes stabilising dihydropyridine intermediates, Pd/Ag‑mediated cyclisations (and efforts to render these catalytic), Heck cyclisations, asymmetric organocatalytic construction of the isoquinuclidine system, and an example of a high‑yielding multistep total synthesis of voacangalactone. The synthesis of 18‑OMe‑coronaridine (127) is highlighted as short, convergent and enantioselective. Analytics and metabolism: For forensic and pharmacokinetic investigations, LC–MS with electrospray ionisation is the method of choice to discriminate iboga alkaloids. Ibogaine is rapidly metabolised to noribogaine (12‑hydroxy‑ibogamine) via CYP2D6; under daylight both ibogaine and noribogaine convert rapidly to other alkaloids (reported photolysis half‑lives of ~81.5 min for ibogaine and ~11 min for noribogaine in the cited study). Pharmacology and toxicology: Ibogaine exhibits a complex pharmacological profile, interacting with μ and κ opioid receptors, σ1/σ2 sites and showing affinity at serotonin and dopamine receptors. Functional studies described ibogaine as a weak μ‑opioid receptor antagonist (no agonist effect in rat thalamic membranes). Inhibition of acetylcholinesterase by ibogaine was found to be weak (IC50 ca. 520 ± 40 μM). Proteomic studies suggest ibogaine induces global metabolic adaptations and antioxidant responses in model systems. Clinically relevant safety concerns are emphasised: reports of fatalities following ibogaine administration exist, with suspected neuro‑ and cardiotoxicity among possible mechanisms; however, the forensic literature does not point to a single clear causal pattern. 18‑OMe‑coronaridine (18‑MC): 18‑MC, a synthetic coronaridine analogue, retains activity in preclinical models of drug self‑administration without tremorigenic side effects. It displays micromolar affinity for κ, μ and σ2 opioid receptors and 5‑HT3, no NMDA or serotonin transporter affinity, and notable activity at α3β4 nicotinic receptors. The compound has also shown activity in reward circuitry and antiparasitic activity against Leishmania amazonensis in preclinical work. A small company has pursued IND‑enabling studies and early human safety work in Brazil. Bioactivity screens: New isolates have been screened in a variety of in vitro assays. Several iboga alkaloids (voacangine, isovoacangine, coronaridine and a coronaridine hydroxyindolenine) inhibited Wnt signalling with IC50s in the ~10 μM range; coronaridine showed cytotoxicity near 2 μM in one assay. Some bisindoles and monomers displayed low‑micromolar cytotoxicity against cancer cell lines, with a few examples compared in potency to cisplatin in vitro. Additional activities reported include CB1 antagonism (submicromolar IC50s), acetylcholinesterase inhibition by select isolates, and antiplasmodial activity for one oxidised tabernaelegantine derivative (IC50 4.4 μM) with low cytotoxicity.

The authors interpret their survey as evidence that iboga alkaloid chemistry and biology remain vibrant fields with unresolved fundamental questions and continued discovery. They emphasise that biosynthetic understanding is incomplete—modern omics and direct characterisation of proposed unstable intermediates are lacking—yet advances in spectroscopic methods and selective X‑ray studies have clarified many new structures. Lotsof and colleagues underline the recurrent problem of absolute configuration assignment for many isolates and note that extraction or chromatographic conditions can produce artefacts that complicate interpretation. In pharmacology, the review places particular weight on the complex, multisite pharmacology of ibogaine and its rapid metabolism to noribogaine, making the origin of both therapeutic and adverse effects difficult to disentangle. Safety concerns—reports of fatalities, possible cardiotoxicity, and neurotoxic signals in animal studies—are presented as a central barrier to clinical development of ibogaine itself. Against that backdrop, the authors highlight 18‑MC as a promising synthetic alternative that retains desirable anti‑addiction activity in preclinical models without some of the tremorigenic liabilities, and note active commercial efforts to advance it through IND‑enabling and early human safety studies. Key limitations acknowledged in the chapter include incomplete biosynthetic data, frequent reliance on spectroscopic rather than synthetic confirmation of absolute stereochemistry, potential artefacts during isolation and purification, limited mechanistic clarity for observed in vitro activities, and a predominance of screening data without extensive in vivo pharmacology or safety characterisation for many new compounds. The authors suggest that future work should combine modern biosynthetic tools, rigorous stereochemical assignment approaches, improved analytical characterisation of plant extracts and metabolites, and more systematic pharmacology and toxicology to assess therapeutic potential and risks.

Iboga‑type alkaloids are a chemically distinctive group of indolomonoterpene alkaloids notable for their diverse biological activities and, particularly, for the long‑standing interest in ibogaine as a potential agent for drug cessation. The authors conclude that, despite safety concerns and incomplete mechanistic understanding, ongoing discoveries of new natural products, advanced structural and synthetic methods, and the development of synthetic analogues such as 18‑MC justify continued research. They frame the work as contributing to the foundation for innovative studies that could, in time, translate into safer and clinically useful therapies inspired by Tabernanthe iboga.