(2-Arylethenyl)-1,3,5-triazin-2-amines as a novel histamine H4 receptor ligands.

Within the constantly growing number of histamine H4 (H4R) receptor ligands there is a large group of azine derivatives. A series of novel compounds in the group of 4-methylpiperazine-1,3,5-triazine-2-amines were designed and obtained. Considered structures were modified at the triazine 6-position by introduction of variously substituted arylethenyl moieties. Their affinities to histamine H4 receptors were evaluated in radioligand binding assays with use of Sf9 cells, transiently expressing human H4R. Pharmacological studies results allowed to identify 4-[(E)-2-(3-chlorophenyl)ethenyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (Ki = 253 nM) as the most potent compound in the present series.

Crypteins--an overlooked piece of peptide systems.

Crypteins, the hidden bioactive sequences, play an important role in the modulation of various biological processes, such as neuronal signaling, angiogenesis, immune response, inflammatory response and cell growth. Proteolytic mechanism leading to the release of crypteins possessing novel biological activities is an important factor for increasing diversity of functional molecules and represents a potential new source of peptide drugs. In this work we would like to focus on crypteins derived from the already known precursors and their potential therapeutic value.

DESI-MS as a tool for direct lipid analysis in cultured cells.

Desorption electrospray ionization may be used as a fast and convenient method for analysis and identification of lipids in the cell culture. Oxidative stress, which usually involves changes in lipids, was used as a model of pathology to show the utility of this analysis methodology. This paper addresses the surface preparation of cell culture slides, induction of oxidative stress, and cell monolayer culture preparation as well as optimization of the analysis. Advantages and drawbacks of the method were also discussed.

Aryl-1,3,5-triazine derivatives as histamine H4 receptor ligands.

A series of novel 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazine derivatives with different aryl substituents in the 6-position was designed, synthesized and evaluated for histamine H4 receptor (H4R) affinity in Sf9 cells expressing human H4R co-expressed with G-protein subunits. Triazine derivative 8 with a 6-(p-chlorophenyl) substituent showed the highest affinity with hH4R Ki value of 203 nM and was classified as an antagonist in cAMP accumulation assay. This compound, identified as a new lead structure, demonstrated also anti-inflammatory properties in preliminary studies in mice (carrageenan-induced edema test) and neither possessed significant antiproliferative activity, nor modulated CYP3A4 activity up to concentration of 25 µM. In order to discuss structure-activity relationships molecular modeling and docking studies were undertaken.

Desorption electrospray ionisation (DESI) for beginners--how to adjust settings for tissue imaging.

RATIONALE: Desorption electrospray ionisation (DESI) is the ambient technique used for surface imaging. Despite its simplicity, the proper use of this technique is not easy, and usually leads to discouragement, especially in the case of biological sample measurements. Here, we present some tips and tricks which may be helpful during a complex process of ion source optimisation to achieve the desired results. METHODS: Rat liver tissue as an example of a biological sample and a surface covered with rhodamine-containing marker were measured using a DESI ion source (OMNIspray source, Prosolia, Indianapolis, IN, USA) connected to a AmaZon ETD ion trap mass spectrometer (Bruker Daltonics, Bremen, Germany). RESULTS: The geometry of the ion source (nebulisation capillary angle, its distance to the surface, and to the MS inlet), and other settings like nebulising gas pressure, solvent flow and capillary voltage, were changed during the optimisation process. The results obtained for different parameters are presented. CONCLUSIONS: Differences between the results and the method of optimisation for biological and non-biological samples were shown. The influence of different parameters on the quality of mass spectra was indicated. Optimal parameters for the tissue and non-biological sample analysis were suggested.

Dynorphin convertases and their functions in CNS.

Neuropeptides play crucial, mediatory roles in many processes that occur in both CNS and PNS. The commonly accepted dogma for the release of bioactive peptides involves cleavage of inactive precursor by sequential action of proteinases recognizing dibasic stretches, followed by truncation of C-terminal Arg/Lys by the carboxypeptidase-like enzyme(s). Dynorphin convertases play an important role in CNS by regulating dynorphins level and also releasing enkephalins, thus maintaining a balance between these neuropeptides and their distinct functions (dynorphins are preferentially bound to kappa receptors and enkephalins are directed toward delta receptors). Knowledge on the cleavage fragments of dynorphins is important for understanding the pharmacological activity of these peptides. As some new data emerged in the literature, we would like to update recent achievements and progress concerning functions of such convertases, inhibitors, and their potential role in future pharmacotherapy.