QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.106.118034v1 322/1/59    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, B. Articles by Webster, N. J. G. Search for Related Content PubMed PubMed Citation Articles by Lin, B. Articles by Webster, N. J. G.

CELLULAR AND MOLECULAR

Neuroprotection by Small Molecule Activators of the Nerve Growth Factor Receptor

Veterans Medical Research Foundation and Veterans Affairs San Diego Healthcare System, San Diego, California (B.L., N.J.G.W.); Department of Medicine, University of California, San Diego, La Jolla, California (N.J.G.W.); and the Department of Chemistry, University of California, Riverside, California (M.C.P., L.D., Z.L., Y.L.)

There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. However, the blood-brain barrier presents a major hurdle in the use of peptide therapeutics. The goal of this study was to identify small molecule, cell-permeable nerve growth factor (NGF) activators. Combinatorial libraries of asterriquinones (>300) and mono-indolyl-quinones (>60) were screened using a 96-well enzyme-linked immunosorbent assay that detects phosphorylated TrkA, the NGF receptor. The libraries were also screened for dose-dependent cytotoxicity. From these screens, we generated quantitative structure-activity relationship models for activity and toxicity, and then we selected two compounds, 2-(6-chloro-1H-indol-3-yl)-5-(2-cyclopropyl-1H-indol-3-yl)-3,6-dihydroxy-[1,4]benzoquinone (1H5) and 2,5-dimethoxy-3-(7-fluoro-1H-indol-3-yl)-[1,4]-benzoquinone (5E5), for further study based on high activity and low toxicity. Compound 1H5 (30 µM) is an asterriquinone that is a moderate TrkA activator (50% the activity of 100 ng/ml NGF), and it shows little toxicity at concentrations up to 100 µM. 1H5 can protect differentiated PC12 neurons from apoptotic cell death induced by NGF withdrawal. Compound 5E5 (30 µM) is a mono-indolyl-quinone that is a very strong activator of TrkA (>200% the activity of 100 ng/ml NGF), and it is nontoxic at concentrations up to 10 µM. Activation of TrkA can be detected at 1 µM 5E5, and 3 to 10 µM 5E5 activates TrkA and extracellular signal-regulated kinase as strongly as a maximal dose of NGF (100 ng/ml). A combination of a low dose of 5E5 (1 µM) with a submaximal dose of NGF (10 ng/ml) promotes neuronal differentiation of PC12 cells. These compounds represent a new class of TrkA activators that could have potential utility in the treatment of neurodegenerative diseases.

Address correspondence to: Dr. Nicholas J. G. Webster, Department of Medicine (0673), Stein Clinical Research Bldg. 201, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673. E-mail: nwebster{at}ucsd.edu

This article has been cited by other articles:

				A. Caporali and C. Emanueli Cardiovascular Actions of Neurotrophins Physiol Rev, January 1, 2009; 89(1): 279 - 308. [Abstract] [Full Text] [PDF]