A Novel Bifunctional µOR Agonist and σ1R Antagonist with Potent Analgesic Responses and Reduced Adverse Effects.

Bifunctional ligands possessing both µOR agonism and σ1R antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the µOR agonism activity of most dual ligands diminishes compared with classical opioids, raising concern about their effectiveness in managing nociceptive pain. In this study, a new class of dual µOR agonist/σ1R antagonist was reported. Through structure-activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar µOR agonism activity (EC50: 0.6 ± 0.2 nM) and good σ1R inhibitory activity (Ki: 363.7 ± 5.6 nM) with excellent selectivity. Compound 4x exhibited robust analgesic effects in various pain models, with significantly reduced side effects. Importantly, compound 4x also possessed good safety profiles and no abnormalities were observed in biological parameters even under a high dosage. Our findings suggest that 4x may be a promising lead compound for developing safer opioids and warrants further in-depth studies.

MiR-299-3p Inhibits Nasopharyngeal Carcinoma Cell Proliferation and Migration by Targeting MMP-2.

Purpose: Nasopharyngeal carcinoma (NPC) is a type of squamous cell carcinoma that originated from the epithelial cells of the nose and throat, and its incidence ranks the first among head and neck tumors. However, NPC has a unique and complex etiology that is not completely understood. MiR-299-3p was discovered to be abnormally expressed in cancers. However, the involvement of miR-299-3p in the incidence and progression of nasopharyngeal cancer remains unknown. Methods: The miR-299-3p expression in nasopharyngeal cancer samples and cell lines was identified using quantitative PCR (qPCR). Nasopharyngeal cancer cells were evaluated for proliferation, migration, and invasion using MTT, colony formation assay, and Transwell invasion assay. MiRBase and TargetScan databases identified the possible miR-299-3p target genes that were confirmed using a dual-luciferase reporter analysis. Additionally, the miR-299-3p target genes were validated by Western blot, colony formation assay, and Transwell assays. Results: It was found that miR-299-3p expression was low in nasopharyngeal cancer tissues and cell lines, according to qPCR data. Cell proliferation, colony formation, and migration were considerably reduced by miR-299-3p overexpression. Furthermore, matrix metalloproteinase 2 (MMP-2) expression was regulated by miR-299-3p, whereas MMP-2 knockdown significantly inhibited the capacity of nasopharyngeal cancer cells to form colonies and migrate. Overexpression of MMP-2 substantially reduced the miR-299-3p inhibitory impact on nasopharyngeal cancer cell migration and colony formation. Conclusion: The miR-299-3p acts as a tumor suppressor gene to suppress the growth and spread of nasopharyngeal cancer by regulating MMP-2 expression. Therefore, miR-299-3p and MMP-2 could be important therapeutic targets for suppressing nasopharyngeal cancer growth and metastasis.

Design, synthesis and biological evaluation of novel procaine derivatives for intravenous anesthesia.

A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f, 6g, 6h, 6o, 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among whichcompound 6h (TI = 2.68)was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 µM.