Discovery of new ERR? agonists regulating dopaminergic neuronal phenotype in SH-SY5Y cells

초록

The discovery of small molecules that regulate specific neuronal phenotypes is important for the development of new therapeutic candidates for neurological diseases. Estrogen-related receptor gamma (ERR gamma), an orphan nuclear receptor widely expressed in the central nervous system (CNS), is closely related to the regulation of neuronal metabolism and differentiation. We previously reported that upregulation of ERR gamma could enhance dopaminergic neuronal phenotypes in the neuroblastoma cell line, SH-SY5Y. In this study, we designed and synthesized a series of new ERR gamma agonists using the X-ray crystal structure of the GSK4716-bound ERR gamma complex and known synthetic ligands. Our new ERR gamma agonists exhibited increased transcriptional activities of ERR gamma. In addition, our molecular docking results supported the experimental findings for ERR gamma agonistic activity of the potent analogue, 5d. Importantly, 5d not only enhanced the expression of dopaminergic neuronal-specific molecules, TH and DAT but also activated the relevant signaling events, such as the CREB-mediated signaling pathway. The results of the present study may provide useful clues for the development of novel ERR gamma agonists for neurological diseases related to the dopaminergic nervous system.

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