title: 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.
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Madalee M
authors.initials: MM
authors.lastname: Gassaway
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Jacques
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Kruegel
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Karpowicz
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Myer
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Sames
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D015394:Molecular Structure; D009457:Neuroglia / Q000187:drug effects*; D051381:Rats
chemical_list: D001952:Bridged-Ring Compounds; D051100:Glial Cell Line-Derived Neurotrophic Factor; C413805:ibogamine; D016222:Fibroblast Growth Factor 2