Structure-based discovery of low molecular weight compounds that stimulate neurite outgrowth and substitute for nerve growth factor

摘要

Olanzapine, an atypical antipsychotic drug, was previously shown to protect neuronal cells against nutrient deprivation and to enhance neurite outgrowth. In an effort to identify small molecules with greater potency, the structure of olanzapine was used as a template to search commercially-available chemical inventories for compounds with similar features. These compounds were evaluated for their ability to protect cells against glutamine deprivation and low serum conditions. Positive compounds, “hits” from initial screening, were then tested for stimulation of neurite outgrowth, alone and in combination with suboptimum concentrations of nerve growth factor (NGF). Numerous neuroprotective compounds (m.w. < 550 Daltons) were identified that significantly stimulated neurite outgrowth in PC12 cells. These included 4′, 6′-diamidino-2-phenylindole (DAPI), a nuclear stain, staurosporine, an antibiotic and kinase inhibitor, and 2-phenylamino-adenosine, an adenosine analogue. The small molecules were comparable to NGF, and in fact, replaced NGF in outgrowth assays. Pharmacophore analysis of the hits led to the design and synthesis of an active compound, LSU-D84, which represents an initial lead for drug discovery efforts