CCR2 receptor antagonists: optimization of biaryl sulfonamides to increase activity in whole blood

A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.     

Chlorophyll formation and the development of photosynthesis in illuminated etiolated pea leaves

Summary The protein synthesis inhibitors chloramphenicol and terramycin, and light of low intensity were used to retard the rate of chlorophyll formation in illuminated dark grown pea leaves. In the control leaves the onset of photosynthesis, as measured by carbon dioxide exchange of the whole leaves, and reduction of ferricyanide and metmyoglobin and photo-oxidation of ascorbate in isolated chloroplasts, was observed after 2–4 hours illumination. The photosynthetic activity of the treated leaves did not commence until 10–12 hours illumination had elapsed. In both the control and treated leaves the onset of photosynthesis occurred when the total chlorophyll content was 0.04 mg/g fresh weight. The precise point of photosynthetic inception was apparently more related to the attainment of a specific total chlorophyl content than to the ratio of chlorophyll a to chlorophyll b. A marked increase in the evolution of carbon dioxide in the light was observed in the treated leaves during the first 10 hours of greening. This observation could not be ascribed to photorespiration since the leaves did not possess an active photosystem. It is suggested that the enhanced respiration may have been due to the light-induced activation of synthetic pathways responsible for the formation of chloroplast constituents.The following abbreviations are used CMU 3(3-chlorophenyl)-1, 1-dimethylurea - DCIP dichlorophenol indophenol - PMS phenazine methosulphate - TRIS 2-amino-2-hydroxymethyl propane-1, 3-diol This work was supported by a Science Research Council studentship granted to R. J. Dowdell and submitted for the degree of Ph. D. of Bath University of Technology.     

MAGT1 messenger RNA-corrected autologous T and natural killer cells for potential cell therapy in X-linked immunodeficiency with magnesium defect,Epstein-Barr virus infection and neoplasia disease

Background aimX-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect' (XMEN) disease is caused by mutations in the magnesium transporter 1 (MAGT1) gene. Loss of MAGT1 function results in a glycosylation defect that abrogates expression of key immune proteins such as the NKG2D receptor on CD8⁺ T and NK cells, which is critical for the recognition and killing of virus-infected and transformed cells, a biomarker for MAGT1 function. Patients with XMEN disease frequently have increased susceptibility to EBV infections and EBV-associated B cell malignancies, for which no specific treatment options are currently available. Experimental transfer of donor EBV-specific cytotoxic T cells may be beneficial but carries the risks of eliciting alloimmune responses. An approach for cell therapy to address viral infections and associated complications that avoids the risks of alloimmunity is needed.MethodsHere the authors assess the feasibility and efficiency of correcting autologous lymphocytes from XMEN patients by MAGT1 mRNA electroporation (EP) that avoids genomic integration and can be scaled for clinical application.Results and conclusionsRestoration of NKG2D expression was demonstrated in XMEN patient lymphocytes after MAGT1 mRNA electroporation that reach healthy donor levels in CD8⁺ T and NK cells at 1-2 days after EP. NKG2D expression persisted at ～50% for 2 weeks after EP. Functionally, mRNA-correction of XMEN NK cells rescued cytotoxic activity also to healthy donor NK cell level. The restored NKG2D receptor expression and function were unaffected by cryopreservation, which will make feasible repeat infusions of MAGT1 mRNA-corrected autologous XMEN CD8⁺ T and NK cells for potential short term therapy for XMEN patients without the risks of alloimmunization.     

Aminomethylpiperazines as selective urotensin antagonists

Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.     

Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.