Abstract
We investigated the agonistic activities of N(4)-(7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl)-N(1),N(1)-diethyl-pentane-1,4-diamine (XIB4035), at the glial cell line-derived neurotrophic factor (GDNF) family receptoralpha-1(GFRalpha-1) in Neuro-2A cells, a mouse neuroblastoma cell line which is a suitable model for investigating functions mediated through GFRalpha-1. XIB4035 concentration-dependently inhibited [(125)I]GDNF binding in Neuro-2A cells with an IC(50) of 10.4 microM. GDNF induced autophosphorylation of Ret protein, and promoted neurite outgrowth in Neuro-2A cells. XIB4035, like GDNF, induced Ret autophosphorylation in the Neuro-2A cells. Moreover, XIB4035 promoted neurite outgrowth in a concentration-dependent manner. These results show that XIB4035 may act as an agonist at GFRalpha-1 receptor complex, and mimic neurotrophic effects of GDNF in Neuro-2A cells. This is an interesting finding showing that a nonpeptidyl small molecule is capable of inducing activation of a receptor that normally bind a relatively large protein ligand such as GDNF.
MeSH terms
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Animals
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Antiparkinson Agents / pharmacology
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Binding, Competitive
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Depression, Chemical
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Drosophila Proteins*
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Mice
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Molecular Structure
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Neoplasm Proteins / metabolism
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Nerve Growth Factors / metabolism*
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Nerve Growth Factors / pharmacology
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Neurites / drug effects
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Neurites / ultrastructure
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Neuroblastoma / pathology
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins / agonists*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-ret
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Quinolines / pharmacology*
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Receptor Protein-Tyrosine Kinases / metabolism
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / ultrastructure
Substances
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Antiparkinson Agents
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Drosophila Proteins
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Gdnf protein, mouse
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Gfra1 protein, mouse
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Neoplasm Proteins
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Nerve Growth Factors
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Proto-Oncogene Proteins
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Quinolines
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XIB 4035
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Ret protein, mouse