Multipotent neurotrophin antagonist targets brain-derived neurotrophic factor and nerve growth factor

The Journal of Pharmacology and Experimental Therapeutics
Joseph K EiblG M Ross

Abstract

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 neurotr...Continue Reading

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Citations

May 13, 2010·Current Pain and Headache Reports·Hsinlin Thomas Cheng
Feb 9, 2016·Progress in Neurobiology·Annette C BakkerMarco Nievo
Dec 18, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Kristen S A SheffieldGregory M Ross
Apr 14, 2016·Pharmacology Research & Perspectives·Eimear O'NeillAndrew Harkin
Apr 27, 2011·Neurourology and Urodynamics·Peter OchodnickýMartin C Michel
Mar 27, 2013·European Journal of Pharmacology·Joseph K EiblGregory M Ross
Oct 30, 2012·Neurochemistry International·Joseph K EiblGregory M Ross
Sep 1, 2016·Biochemical and Biophysical Research Communications·Reka ChakravarthyAdrienne M Gorman
Oct 10, 2012·Nature Reviews. Urology·Peter OchodnickyFrancisco Cruz
Oct 2, 2015·Journal of Biomolecular Screening·Allison E KennedyGregory M Ross
Feb 16, 2013·ACS Medicinal Chemistry Letters·Eunhwa KoKevin Burgess
Nov 23, 2021·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Win Min Oo, David J Hunter

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