Neuroblastoma (NB) often causes spontaneously regression, and can mature to ganglioneuroma. The form with the most favorable prognosis expresses high levels of TrkA, a high-affinity receptor for nerve growth factor (NGF), whereas advanced NB and associated cell lines have abnormalities in the NGF/TrkA signaling pathway. A novel cyclophane, cyclophane pyridine (CPPy), was designed to conserve the tyrosine phosphorylation of TrkA, thereby enhancing NGF/TrkA signal transduction. We investigated whether this compound improved NGF-induced tyrosine phosphorylation of the Y490 domain of TrkA and conserved the expression of an early gene (c-fos) in human NB cell lines (IMR-32 and NB-39). As determined by Western blotting, TrkA (Y490) phosphorylation was enhanced by the combination of CPPy (10(-8) M) and NGF (100 ng/ml) compared with NGF alone. CPPy also conserved NGF-induced c-fos mRNA expression. Moreover, CPPy induced the morphological differentiation of NB cells, leading to expression of the neuronal marker gene GAP-43. These data suggest that CPPy can induce the differentiation of NB cell lines by facilitating NGF-induced TrkA/Ras/MAPK signal transduction, and may therefore be an effective therapeutic agent for NB.