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

• Published in: ACS chemical biology 2016-01, Vol.11 (1), p.77-87
• Main Authors: Gassaway, Madalee M., Jacques, Teresa L., Kruegel, Andrew C., Karpowicz, Richard J., Li, Xiaoguang, Li, Shu, Myer, Yves, Sames, Dalibor
• Format: Article
• Language: English
• Subjects: Animals; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Fibroblast Growth Factor 2 - pharmacology; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Molecular Structure; Neuroglia - drug effects; Rats
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.5b00678

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.