5408-15-1Relevant articles and documents
Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment
Ouyang, Liang,Zhang, Lan,Zhang, Shouyue,Yao, Dahong,Zhao, Yuqian,Wang, Guan,Fu, Leilei,Lei, Peng,Liu, Bo
supporting information, p. 2776 - 2792 (2018/04/23)
UNC-51-like kinase 1 (ULK1), the yeast Atg1 ortholog, is the sole serine-threonine kinase and initiating enzyme in autophagy, which may be regarded as a target in Parkinson's disease (PD). Herein, we discovered a small molecule 33i (BL-918) as a potent activator of ULK1 by structure-based drug design. Subsequently, some key amino acid residues (Arg18, Lys50, Asn86, and Tyr89) were found to be crucial to the binding pocket between ULK1 and 33i by site-directed mutagenesis. Moreover, we found that 33i induced autophagy via the ULK complex in SH-SY5Y cells. Intriguingly, this activator displayed a cytoprotective effect on MPP+-treated SH-SY5Y cells, as well as protected against MPTP-induced motor dysfunction and loss of dopaminergic neurons by targeting ULK1-modulated autophagy in mouse models of PD. Together, these results demonstrate the therapeutic potential to target ULK1, and 33i, the novel activator of ULK1, may serve as a candidate drug for future PD treatment.
SEROTONIN REUPTAKE INHIBITORS
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Page/Page column 25, (2010/02/14)
A serotonin reuptake inhibitor which can be used in the treatment of depression and which has a decreased occurrence of unwanted side effects. The serotonin reuptake inhibitors are bi-functional organic molecules which combine serotonin transporter reuptake inhibition with serotonin (5-HT,such as 5-HT2A) receptor antagonism in one molecular entity. The serotonin-selective reuptake inhibitor (SSRI) homologue portion of the molecule shows an affinity to the serotonin reuptake transporter (SERT) and has antidepressant properties. The piperazine or piperidine portion of the molecule demonstrates an affinity to 5-HT receptors and restores the undesired side effects of SSRIs.