作者: Qian, Hai ; Song, Depu ; Qiao, Zhenrui ; He, Wenya ; Chen, Yingda ; Tian, Zhiyong ; Guo, Ning ; Yan, Lin ; Wang, Guohao ; Zhang, Yang ; Wang, Qiang ; Shao, Lulian ; Qiao, Yue

Transient receptor potential vanilloid 1 (TRPV1) antagonists can inhibit the transmission of nociceptive signals from the peripheral to the central nervous system (CNS), providing a new strategy for pain relief. In this work, in order to develop potent, CNS-penetrant, and orally available TRPV1 antagonists, three series of novel molecules based on the key pharmacophore structures of classic TRPV1 ligands SB-705498 and MDR-652 were designed and synthesized. Through systematic in vitro and in vivo bioassays, (S)-N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (7q) was finally identified, which had enhanced TRPV1 antagonistic activity (IC₅₀ (capsaicin) = 2.66 nM), excellent CNS penetration (brain/plasma ratio = 1.66), favorable mode-selectivity, good bioavailability, and no side effects of hyperthermia. Molecular docking and dynamics studies indicated that the high binding affinity of compound 7q to TRPV1 was related to multiple interactions, which resulted in significant conformational changes of TRPV1. Overall, our findings have led to a potent, mode-selective, and CNS-penetrant TRPV1 antagonist as a valuable lead for development of novel TRPV1 antagonists.

2019-11-01·Cancer Biomarkers3区 · 医学

MiR-652 serves as a prognostic biomarker in gastric cancer and promotes tumor proliferation, migration, and invasion via targeting RORA

3区 · 医学

Article

作者: Li, Juncheng ; Zou, Xiaoming

PURPOSEMicroRNAs (miRNAs) have been reported to be involved in tumorigenesis. The aim of this study was to investigate the functional role and prognostic value of miR-652 in gastric cancer (GC).METHODSQuantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression levels of miR-652 in human GC tissue samples and GC cell lines. The Kaplan-Meier survival curves and Cox regression analysis were performed to measure the prognostic value of miR-652 in GC. The tumor cell proliferation capacity was estimated by MTT assay, and cell migration and invasion were assessed by Transwell assays. The luciferase reporter assay was performed to confirm the target gene of miR-652.RESULTSMiR-652 was significantly elevated in GC tissues and cell lines (all P< 0.001). And the expression level of miR-652 was significantly associated with TNM stage and lymph node metastasis (all P< 0.05). GC patients with high expression of miR-652 had a shorter overall survival rate than those with low miR-652 expression (log-rank P< 0.001). The miR-652 and TNM stage were proven to be independent prognostic predictors for the GC patients. Overexpressing miR-652 could enhance cell proliferation, migration and invasion (all P< 0.01). RORA was proved to be the target gene of miR-652.CONCLUSIONMiR-652 functions as an oncogene in GC and promotes tumor progression via targeting RORA. MiR-652 might be a novel predictive marker for the poor prognosis of GC patients.

International Journal of Molecular Sciences

Three-Dimensional Quantitative Structure–Activity Relationship Study of Transient Receptor Potential Vanilloid 1 Channel Antagonists Reveals Potential for Drug Design Purposes

Article

作者: Spinsanti, Giacomo ; Gianibbi, Beatrice ; Spiga, Ottavia ; Visibelli, Anna

Transient receptor potential vanilloid 1 (TRPV1) was reported to be a putative target for recovery from chronic pain, producing analgesic effects after its inhibition. A series of drug candidates were previously developed, without the ability to ameliorate the therapeutic outcome. Starting from previously designed compounds, derived from the hybridization of antagonist SB-705498 and partial agonist MDR-652, we performed a virtual screening on a pharmacophore model built by exploiting the Cryo-EM 3D structure of a nanomolar antagonist in complex with the human TRPV1 channel. The pharmacophore model was described by three pharmacophoric features, taking advantage of both the bioactive pose of the antagonist and the receptor exclusion spheres. The results of the screening were implemented inside a 3D-QSAR model, correlating with the negative decadic logarithm of the inhibition rate of the ligands. After the validation of the obtained 3D-QSAR model, we designed a new series of compounds by introducing key modifications on the original scaffold. Again, we determined the compounds’ binding poses after alignment to the pharmacophoric model, and we predicted their inhibition rates with the validated 3D-QSAR model. The obtained values resulted in being even more promising than parent compounds, demonstrating that ongoing research still leaves much room for improvement.

100 项与 MDR-652 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
背痛	临床1期	韩国	Hyper Corp., Inc.	2022-01-30
糖尿病性神经病变	临床前	韩国	Hyper Corp., Inc.	2022-01-30
疱疹后神经痛	临床前	韩国	Hyper Corp., Inc.	2022-01-30