Bruno González

Ibogaine is the main psychoactive alkaloid produced by the iboga tree (Tabernanthe iboga) that has a unique therapeutic potential across multiple indications, including opioid dependence, substance use disorders, depression, anxiety, posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI). We systematically examined the effects of ibogaine, its main metabolite noribogaine, and a series of iboga analogs at monoamine neurotransmitter transporters, some of which have been linked to the therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with submicromolar potency in cell-based fluorometry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. Examining the uptake and release of radiolabeled serotonin in isolated brain synaptic vesicles, we confirmed that ibogaine and noribogaine act as inhibitors of VMAT2 and showed that noribogaine induces partial serotonin release from synaptic vesicles. Noribogaine does not compete with the binding of dihydrotetrabenazine, an established VMAT2 inhibitor, indicating that noribogaine engages the VMAT2 transporter at a distinct binding site or conformational state. The iboga compounds also inhibit the plasma membrane monoamine transporters (MATs), prominently including the serotonin transporter (SERT), and a novel iboga target, the organic cation transporter 2 (OCT2). SERT transport inhibition was demonstrated in serotonin axons and somata in mouse brain slices and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine, oxa-noribogaine, and several analogs displayed dual inhibition of VMAT2 and SERT with comparable potencies, a relatively uncommon activity in the pharmacopoeia of monoamine transporter inhibitors, and were hence labeled as "Synaptic Reuptake Inhibitors" ("SynRIs"). The SynRI profile provides an explanatory model for previously reported neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the grand complexity of the iboga pharmacology, which we termed "matrix pharmacology". The matrix pharmacology hypothesis is outlined and used to conceptualize why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT_2A receptor (5-HT_2AR) in mice. In that regard, we used male and female, 5-HT_2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT_2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT_2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT_2AR blunted noribo-mediated responses to NMDA synaptic transmission.

The iboga alkaloids scaffold shows great potential as a pharmacophore in drug candidates for the treatment of neuropsychiatric disorders. Thus, the study of the reactivity of this type of motif is particularly useful for the generation of new analogs suitable for medicinal chemistry goals. In this article, we analyzed the oxidation pattern of ibogaine and voacangine using dioxygen, peroxo compounds, and iodine as oxidizing agents. Special focus was placed on the study of the regio- and stereochemistry of the oxidation processes according to the oxidative agent and starting material. We found that the C₁₆-carboxymethyl ester present in voacangine stabilizes the whole molecule toward oxidation in comparison to ibogaine, especially in the indole ring, where 7-hydroxy- or 7-peroxy-indolenines can be obtained as oxidation products. Nevertheless, the ester moiety enhances the reactivity of the isoquinuclidinic nitrogen to afford C₃-oxidized products through a regioselective iminium formation. This differential reactivity between ibogaine and voacangine was rationalized using computational DFT calculations. In addition, using qualitative and quantitative NMR experiments combined with theoretical calculations, the absolute stereochemistry at C₇ in the 7-hydroxyindolenine of voacangine was revised to be S, which corrects previous reports proposing an R configuration.