The specific aims of the research described in this application is to develop novel potent and selective small molecule potentiators of NGF dependent activity in neurons, and to characterize their mechanisms of action n promoting neuronal differentiation and survival with regards to new pathways and cellular targets. The objectives in the long-term are to develop invaluable tools to better understand the general mechanisms of activity potentiation and the roles of NGF in fostering the development of neural processes. Identified leads with acceptable therapeutic profiles will progress through SAR with the ultimate goal to develop therapeutic agents that prevent or delay the onset of neurodegeneration caused by defects in molecular and chemical cues that initiate and sustain neurite extension. This research will utilize the approaches of chemoinformatics and HTS to identify novel structures and molecules with core chemical scaffolds that are similar to known potentiators of NGF-dependent neurite extension of natural products origin from a chemical library of small molecules. Active compounds will be characterized for potency, efficacy, selectivity, and specificity in neuronal cell lineages to identify lead compounds. Studies on the mechanism of actions of leads compounds will be initiated to establish novel pathways and cellular targets that interact with identified leads. Successful development of NGF potentiators with therapeutic values will have a tremendous impact in modifying the outcome of age-related neurodegenerative diseases and other dementias.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM081092-04
Application #
7916674
Study Section
Special Emphasis Panel (ZGM1-MBRS-1 (SC))
Program Officer
Gindhart, Joseph G
Project Start
2007-09-24
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2010
Total Cost
$102,807
Indirect Cost
Name
North Carolina Central University
Department
Type
Organized Research Units
DUNS #
783691801
City
Durham
State
NC
Country
United States
Zip Code
27707
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Williams, Alfred L; Dandepally, Srinivasa R; Gilyazova, Nailya et al. (2010) Microwave-assisted synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252): a new potentiator of Nerve Growth Factor (NGF)-induced neurite outgrowth. Tetrahedron 66:9577-9581
Clement, Ceil├ęssia M; Dandepally, Srinivasa R; Williams, Alfred L et al. (2009) A synthetic analog of verbenachalcone potentiates NGF-induced neurite outgrowth and enhances cell survival in neuronal cell models. Neurosci Lett 459:157-61