Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound

Abstract

Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCγ in C6 glioma cells.

A non-hallucinogenic psychedelic analogue with therapeutic potential

“…We reasoned that systematic deletion of these key structural elements would reveal the essential features of ibogaine’s psychoplastogenic pharmacophore. By adapting chemistry developed by Sames and co-workers, 17 we were able to access a series of isoquinuclidine-containing compounds ( 8 – 11 ) that lacked the tetrahydroazepine and/or indole characteristic of ibogaine ( Extended Data Fig. 1a ).…”

Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

“…Accordingly, another study from the same research group showed that the intra-VTA infusion of noribogaine induced a long-lasting decrease in ethanol self-administration (Carnicella et al, 2010). Further, ibogaine-derived synthetic derivatives were recently shown to induce the release of GDNF in vitro , in established cell line systems (Gassaway et al, 2016). These observations formed the basis for a new rationale to explain the long-lasting effects of ibogaine; i.e., the induction of GDNF by ibogaine/noribogaine may activate an autocrine loop, leading a long-term synthesis and release of GDNF (that persists beyond elimination of both substances).…”

Bridging the Gap: Plant‐Endophyte Interactions as a Roadmap to Understanding Small‐Molecule Communication in Marine Microbiomes

“…This is a well‐known phenomenon in animal parasites such as Toxoplasma gondii which specifically reduces fear of predators in rodents through production of tyrosine hydroxylase and consequent accumulation of dopamine. Reductions in self‐preservation instincts facilitate its spread to feline hosts . Similar modulation of host physiology by pathogens has been documented in plants.…”