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The Journal of Neuroscience, May 17, 2006, 26(20):5288-5300; doi:10.1523/JNEUROSCI.3547-05.2006

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Development/Plasticity/Repair
Small, Nonpeptide p75^NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

Stephen M. Massa,^1,* Youmei Xie,^2,* Tao Yang,² Anthony W. Harrington,⁴ Mi Lyang Kim,⁴ Sung Ok Yoon,⁴ Rosemary Kraemer,⁵ Laura A. Moore,² Barbara L. Hempstead,⁶ and Frank M. Longo^2,3

¹Department of Neurology and Laboratory for Computational Neurochemistry and Drug Discovery, San Francisco Veterans Affairs Medical Center, and Department of Neurology, University of California, San Francisco, San Francisco, California 94121, ²Department of Neurology and ³University of North Carolina Neuroscience Center, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina 27599, ⁴Department of Cellular and Molecular Biochemistry and Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210, and ⁵Department of Pathology and ⁶Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10016

Correspondence should be addressed to either of the following: Dr. Frank M. Longo, Department of Neurology and Neurological Sciences A343, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, Email: longo{at}stanford.edu or Dr. Stephen M. Massa, Department of Neurology (127), San Francisco Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, Stephen.Massa{at}ucsf.edu

Studies showing that neurotrophin binding to p75^NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75^NTR in a monovalent manner, raise the possibility that small molecule p75^NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75^NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75^NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75^NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75^NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.

Key words: small molecules; nerve growth factor; brain-derived neurotrophic factor; p75; neurotrophin receptor; hippocampal neurons; oligodendrocytes

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Received Aug. 22, 2005; revised April 2, 2006; accepted April 3, 2006.

Correspondence should be addressed to either of the following: Dr. Frank M. Longo, Department of Neurology and Neurological Sciences A343, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, Email: longo{at}stanford.edu or Dr. Stephen M. Massa, Department of Neurology (127), San Francisco Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, Stephen.Massa{at}ucsf.edu

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