Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe.

Despite its essential role in the (patho)physiology of several diseases, CB2R tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CB2R agonist probe employing structure-based reverse design. It commences with a highly potent, preclinically validated ligand, which is conjugated to a silicon-rhodamine fluorophore, enabling cell permeability. The probe is the first to preserve interspecies affinity and selectivity for both mouse and human CB2R. Extensive cross-validation (FACS, TR-FRET and confocal microscopy) set the stage for CB2R detection in endogenously expressing living cells along with zebrafish larvae. Together, these findings will benefit clinical translatability of CB2R based drugs

Probing 2H-indazoles as template for SGK1, Tie2 and SRC kinase inhibitors

The broader and systematic application of a novel scaffold is often hampered by the unavailability of a short and reliable synthetic access. We investigated a new strategy for the design and synthesis of an array of N2-substituted aza-2H-indazole derivatives as potential kinase inhibitors. Guided by a rational ligand alignment approach to qualify the so far underrepresented aza-2H-indazole scaffold, indazoles were connected in N2-position with a phenyl spacer and an arylsulfonamide or amide linkage. Initial profiling against a panel of 30 kinases confirmed the in silico predicted selectivity bias. A synthesized focused library of 52 different aza-2H-indazole derivatives showed good initial selective inhibition against SGK1, Tie2 and SRC kinase with the best representatives having IC50s in the range of up to 500 nM. In a comparative computational study, these data were analyzed and rationalized in the light of docking studies

Cannabinoid receptor type 2 ligands: an analysis of granted patents since 2010

The G-protein-coupled cannabinoid receptor type 2 (CB(2)R) is a key element of the endocannabinoid (EC) system. EC/CB(2)R signaling has significant therapeutic potential in major pathologies affecting humans such as allergies, neurodegenerative disorders, inflammation or ocular diseases. CB(2)R agonism exerts anti-inflammatory and tissue protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney, lung and neurodegenerative disorders. Existing ligands can be subdivided into endocannabinoids, cannabinoid-like and synthetic CB(2)R ligands that possess various degrees of potency on and selectivity against the cannabinoid receptor type 1. This review is an account of granted CB(2)R ligand patents from 2010 up to the present, which were surveyed using Derwent Innovation®

Spectroscopic and Chemometric Comparison of Local River Sands with the Aggregate Component in Mortars from Ancient Roman Buildings Located in the X Regio Between the Livenza and Tagliamento Rivers, Northeast Italy

A combined spectroscopic–chemometric approach is used to investigate the possible sources of material exploited by the Romans to build four domus and a public thermae complex (I century BC–II century AD) located in the X Regio portion between the rivers Livenza and Tagliamento in northeast Italy. The rounded grain shapes observed in the aggregates recovered from the mortar fragments suggest that the rivers flowing close to the archaeological sites are the most likely sources of material. Coarse-grained sediment samples from nine rivers and streams in this area are examined and their similarities to the aggregate samples evaluated. The diffuse reflection Fourier transform infrared (FT-IR) spectra of the sand samples in the 63–420 µm fraction, consisting mainly of carbonates and silicates, are studied and compared in suitable spectral ranges through principal components analysis. As an additional step, the relationship between the most significant scores plots and the composition of the samples is investigated using appropriate descriptive indexes obtained from the spectra. The analysis performed on the river sand spectra alone shows that the samples from the easternmost Lemene and Tagliamento rivers present a behavior distinct from that of the western rivers (Cosa, Livenza, Meduna, Meschio, and Noncello), in agreement with their present location and past history. All the aggregate spectra investigated are compatible with the spectral characteristics of the samples from the Tagliamento and Lemene rivers, except for those from the Torre di Pordenone site, which are more similar to the sand spectra of the western rivers