MEDICINAL CHEMISTRY RESEARCH
·
2021
·Vol. 30
·期 11
·2069-2089
·
IF 1.965
Yu Ming-jun,Li Chao,He Meng,Zhu Yu-ting,Yang Rui,Deng Sheng-song,Meng Xiao-ming,Yao Ri-sheng
Gastrin-releasing peptide (GRP)/gastrin-releasing peptide receptor (GRPR) have various physiological effects, and many studies report that GRPR is a potential anticancer target. Pd176252 is a typical small-molecule GRPR antagonist that exhibits anti-proliferation activity against most cancers. In this study, 31 novel Pd176252 analogues were designed, synthesized, and evaluated for anti-proliferation activity against human prostate cancer (PC3), mouse pancreatic cancer (Pan02), human gastric cancer (HGC-27), and hepatocellular carcinoma (HepG2) cell lines. Of all the compounds evaluated, 5a and 6e showed better anti-proliferation activity compared to Pd176252 against PC3 (half-maximal inhibitory concentration [IC 50 ] = 4.97 and 9.88 μM, respectively), Pan02 (IC 50 = 4.36 and 2.50 μM, respectively), and HGC-27 (IC 50 = 4.36 and 2.50 μM, respectively), cell lines. Moreover, combining 5a or 6e with a histone deacetylase (HDAC) inhibitor further improved the in vitro anti-proliferation activity. Further research showed that 5a caused HGC-27 cell apoptosis by downregulating Bcl-2 and upregulating Bax. In addition, a molecular docking analysis showed that compounds 5a and 6e could bind to GRPR. In conclusion, compounds 5a and 6e are novel GRPR antagonists with potent anticancer activity.
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
高影响因子
Cell Reports
·
2025
·
IF 6.9
Kangtai Xu,Xuefei Liu,Qian Zeng,Yaqi Liu,Leyan Shan,Luyao Ji,Yifei Wu,Jiawei Wu,Yiming Chen,Yitong Li,Songqiang Huang,Changyu Jiang,Xin Hong,Chaoran Wu,Zilong Wang
Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal cannabinoid receptor type 2 (CB 2 R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB 2 R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA sequencing and molecular mechanistic studies suggest that CB 2 R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB 2 R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB 2 R activation in microglia alleviates chronic itch via neuro-immune interactions.
研究领域:
神经科学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2023
·
IF 7.7
Zhi-Jun Zhang,Han-Yu Shao,Chuan Liu,Hao-Lin Song,Xiao-Bo Wu,De-Li Cao,Meixuan Zhu,Yuan-Yuan Fu,Juan Wang,Yong-Jing Gao
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
研究领域:
神经科学
·
药理学
·
疼痛研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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