title: XIB4035, a novel nonpeptidyl small molecule agonist for GFRalpha-1.
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.
authors.affiliation: CNS Diseases Research, Medicinal Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Saitama, Saitama 330-8530, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tokugawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishiguchi
authors.forename: Takumi
authors.initials: T
authors.lastname: Sekine
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sakai
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ueki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okuyama
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001667:Binding, Competitive; D003864:Depression, Chemical; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051379:Mice; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D011804:Quinolines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure
chemical_list: D000978:Antiparkinson Agents; D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009363:Neoplasm Proteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C470912:XIB 4035; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse