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