Multipotent neurotrophin antagonist targets brain-derived neurotrophic factor and nerve growth factor.
Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are members of the neurotrophin family that normally play a role in the development and maintenance of the nervous system. However, neurotrophin dysregulation has been implicated in several neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuropathic pain, depression, and substance abuse. Despite their central role in the nervous system, neurotrophins have proved to be an elusive pharmacological target. Here, we describe a novel multipotent neurotrophin antagonist, 3-[(5E)-4-oxo-5-[[5-(4-sulfamoylphenyl)-2-furyl]methylene]-2-thioxo-thiazolidin-3-yl]propanoic acid (Y1036). Y1036 binds BDNF (K(D) = 3.5 +/- 0.3 microM) and NGF (K(D) = 3.0 +/- 0.4 microM) preventing either BDNF or NGF from interacting with their obligate receptor(s). Y1036 prevents both BDNF- and NGF-mediated trk activation, downstream activation of the p44/42 mitogen-activated protein kinase pathway, and neurotrophin-mediated differentiation of dorsal-root ganglion sensory neurons. Identification of a BDNF- and NGF-specific antagonist is of considerable interest in the study and treatment of diseases where dysregulation of multiple neurotrophins has been implicated.
Eibl
J K
JK
Northern Ontario School of Medicine, Sudbury, ON, Canada, P3E 2C6.
Chapelsky
S A
SA
Ross
G M
GM
D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000493:pharmacokinetics* / Q000494:pharmacology
C547152:3-((5E)-4-oxo-5-((5-(4-sulfamoylphenyl)-2-furyl)methylene)-2-thioxo-thiazolidin-3-yl)propanoic acid; D019208:Brain-Derived Neurotrophic Factor; D011422:Propionates; D053778:Thiazolidines; D020932:Nerve Growth Factor