Transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel, is the predominant mammalian cold temperature thermosensor and it is activated by cold temperatures and cooling compounds, such as menthol and icilin. Because of its role in cold allodynia, cold hyperalgesia and painful syndromes TRPM8 antagonists are currently being pursued as potential therapeutic agents for the treatment of pain hypersensitivity. Recently TRPM8 has been found in subsets of bladder sensory nerve fibres, providing an opportunity to understand and treat chronic hypersensitivity. However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we applied two virtual screening strategies to find new, clinics suitable, TRPM8 inhibitors. This strategy enabled us to identify naphthyl derivatives as a novel class of potent and selective TRPM8 inhibitors. Further characterization of the pharmacologic properties of the most potent compound identified, compound 1, confirmed that it is a selective, competitive antagonist inhibitor of TRPM8. Compound 1 also proved itself active in a overreactive bladder model in vivo. Thus, the novel naphthyl derivative compound identified here could be optimized for clinical treatment of pain hypersensitivity in bladder disorders but also in different other pathologies.
NF-B and activator protein 1 (AP-1) are dimeric transcription factors involved in transcriptional regulation in many cells, including neurons. We have examined their activity during mouse cerebellum development, a postnatal process starting just after birth and completed by the fourth postnatal (PN) week. The activity of these factors was analyzed by binding of nuclear extracts to a synthetic oligonucleotide representing the B site of human immunodeficiency virus or the AP-1 site of the urokinase promoter. NF-B activity was observed from 7 PN, was restricted to the developing cerebellum, and was not observed in the early postnatal neocortex and hippocampus. On the other hand, AP-1 activity was not found in cerebellum but was present in both neocortex and hippocampus. Moreover, a B-driven transgene was found to be increasingly expressed in the cerebellum from 5 PN to 10 PN but not in the adult. The regulation of NF-B activation in mouse cerebellum was analyzed by intraperitoneal injection of glutamate receptor antagonists to 9 PN mice, which abolished NF-B-binding activity, suggesting an endogenous loop of glutamate receptor activation. Glutamate receptor agonists, on the other hand, induced NF-B nuclear translocation in the cerebellum of 5 PN mice, which is a stage in which NF-B is not yet endogenously activated. This effect was specific for NF-B and not observed for AP-1. In adult mice, NF-B activity was absent in the cerebellum and was not induced by intraperitoneal injection of glutamate receptor agonists. These data show that NF-B is specifically activated during cerebellum development and indicate an important role of glutamate receptors in this process.
Lipopolysaccharide (LPS)-induced differentiation of the murine pre-B cell line 70Z/3 is a model for pre-B to B cell differentiation and has been used to show that the transcription factor NF-U UB is essential to induce the expression of the IgU U gene. We have investigated the mechanism involved in late stages of the process when all cells have reached a more mature B phenotype, i.e. beyond 48 up to 96 h of LPS treatment. NF-U UB binding activity was induced at early times by LPS treatment, but its DNA binding activity disappeared after 84 h of LPS treatment. Accumulation of IU UBK K protein in the nucleus correlated with the disappearance of NF-U UB activity at 72, 84 and 96 h, and treatment of nuclear extracts of 72^96 h LPStreated cells with Na-deoxycholate restored NF-U UB binding activity. The data indicate that NF-U UB, while important to initiate the process of IgU U gene transcription in 70Z/3 pre-B cells, is no longer required for its maintenance in differentiated 70Z/3 cells.z 1998 Federation of European Biochemical Societies.
The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC50 = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in Escherichia coli ATCC BAA-2523 β-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs.
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