a b s t r a c tThe pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

Currently, there is mounting evidence that intermolecular receptor-receptor interactions may result in altered receptor recognition, pharmacology and signaling. Heterobivalent ligands have been proven useful as molecular probes for confirming and targeting heteromeric receptors. This report describes the design and synthesis of novel heterobivalent ligands for dopamine D -like receptors (D -likeR) and the μ-opioid receptor (μOR) and their evaluation using ligand binding and functional assays. Interestingly, we identified a potent bivalent ligand that contains a short 18-atom linker and combines good potency with high efficacy both in β-arrestin 2 recruitment for μOR and MAPK-P for D R. Furthermore, this compound was characterized by a biphasic competition binding curve for the D R-μOR heterodimer, indicative of a bivalent binding mode. As this compound possibly bridges the D R-μOR heterodimer, it could be used as a pharmacological tool to further investigate the interactions of D R and μOR.

In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D receptor (DR). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing DR and mGluR5 compared to cells solely expressing DR. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. Additionally, 22a exhibited a 5-fold higher mGluR5 affinity than its monovalent precursor 21a in cells coexpressing DR and mGluR5. These results indicate that 22a is able to bridge binding sites on both receptors constituting the heterodimer. Likewise, cAMP assays revealed that 22a had a 4-fold higher potency in stable DR and mGluR5 coexpressing cell lines than 1. Furthermore, molecular modeling reveals that 22a is able to simultaneously bind both receptors by passing between the TM5-TM6 interface and establishing six protein-ligand H-bonds.

High-conductive phosphorus-doped Si nanocrystals/SiO2(nc-Si/SiO2) multilayers are obtained, and the formation of Si nanocrystals with the average crystal size of 6 nm is confirmed by high-resolution transmission electron microscopy and Raman spectra. The temperature-dependent carrier transport behaviors of the nc-Si/SiO2 films are systematically studied by which we find the shift of Fermi level on account of the changing P doping concentration. By controlling the P doping concentration in the films, the room temperature conductivity can be enhanced by seven orders of magnitude than the un-doped sample, reaching values up to 110 S/cm for heavily doped sample. The changes from Mott variable-range hopping process to thermally activation conduction process with the temperature are identified and discussed.