Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB? receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB? receptor-mediated cardiovascular depression is related to increased G protein coupling of CB? receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH?/? mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.     

Size-dependent reactions of ammonium bisulfate clusters with dimethylamine

The reaction kinetics of ammonium bisulfate clusters with dimethylamine (DMA) gas were investigated using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Clusters ranged in size from 1 to 10 bisulfate ions. Although displacement of the first several ammonium ions by DMA occurred with near unit efficiency, displacement of the final ammonium ion was cluster size dependent. For small clusters, all ammonium ions are exposed to incoming DMA molecules, allowing for facile exchange ("surface" exchange). However, with increasing cluster size, an ammonium ion can be trapped in an inaccessible region of the cluster ("core" exchange), thereby rendering exchange difficult. DMA was also observed to add onto existing dimethylaminium bisulfate clusters above a critical size, whereas ammonia did not add onto ammonium bisulfate clusters. The results suggest that as the cluster size increases, di-dimethylaminium sulfate formation becomes more favorable. The results of this study give further evidence to suggest that ambient sub-3 nm diameter particles are likely to contain aminium salts rather than ammonium salts.     

Bio-templated CdSe nanoparticle synthesis in a cage shaped protein, Listeria-Dps, and their two dimensional ordered array self-assembly

We report here, for the first time, a biotemplated synthesis of uniform CdSe nanoparticle (4.1 ± 0.5 nm) and a fabrication of two-dimensional CdSe nanoparticles (over one micrometre) with nanometric gaps by cage-like protein, Listeria-Dps.     

Synthesis of alpha-amino acids by reaction of aziridine-2-carboxylic acids with carbon nucleophiles

A variety of homochiral alpha-amino acids have been prepared in good yield via regioselective reaction of higher order cuprates with (2S)-N-para-toluenesulfonylaziridine-2-carboxylic acid 4. The reaction was much less regioselective and low yielding when higher order cuprates were reacted with the more hindered aziridine carboxylic acid 30, the principal products being protected beta-amino acids. Reaction of lithium trimethylsilylacetylide with the aziridine acid 30, however, gave a protected alpha-amino acid which was converted to the protected isoleucine ester 37.     

Synthesis of (2S,3S)-[3-(2)H1]-4-methyleneglutamic acid and (2S,3R)-[2,3-(2)H2]-4-methyleneglutamic acid

(2S,3S)-[3-(2)H1]-4-Methyleneglutamic acid 1a and (2S,3R)-[2,3-(2)H2]-4-methyleneglutamic acid 1b have been synthesised for use in biosynthetic and metabolic studies.     

Potential cancer chemopreventive agents from Arbutus unedo

A phytochemical study of the petroleum ether and ethyl acetate extracts of the entire plant of Arbutus unedo led to the isolation of a new sterol, 7beta-hydroxystigmast-4-en-3-one (1), and nine known compounds of the flavan, steroid, and terpenoid types. The structure of 1 was determined by spectroscopic data interpretation in combination with molecular modeling calculations. The absolute stereochemistry of C-7 was assigned as S for compound 1 based on the obtained CD spectral data. Activity in the JB6 cell transformation assay was found for pomolic acid 3-acetate (4). All isolates obtained were evaluated in a cyclooxygenase-2 (COX-2) inhibition assay.     

Functionalized single graphene sheets derived from splitting graphite oxide

A process is described to produce single sheets of functionalized graphene through thermal exfoliation of graphite oxide. The process yields a wrinkled sheet structure resulting from reaction sites involved in oxidation and reduction processes. The topological features of single sheets, as measured by atomic force microscopy, closely match predictions of first-principles atomistic modeling. Although graphite oxide is an insulator, functionalized graphene produced by this method is electrically conducting.     

Inertial suppression of protein dynamics in a binary glycerol-trehalose glass

The traditional approach used to predict the ability of a glassy matrix to maximally preserve the activity of a protein solute is the glass transition temperature (T(g)) of the glass. Recently it has been shown that the addition of a low T(g) diluent (glycerol) can rigidify the structure of a high T(g) glassy matrix in binary glycerol-trehalose glasses. The optimal density of glycerol in trehalose minimizes the average mean square displacements of non-exchangeable protons in the glass samples. The amount of glycerol added to a trehalose glass coincides with the maximal recovery of biological activity in a separate study using similar binary glass samples. In this study, we use molecular dynamics (MD) simulations to investigate the dynamics of a hydrated protein encased in glycerol, unary trehalose and binary glycerol-trehalose glasses. We have found that we are able to reproduce the rigidification of the glycerol-trehalose glassy matrix and that there is a direct correlation between bulk glass dynamics and the extent of atomic fluctuation of protein atoms. The detailed microscopic picture that emerges is that protein dynamics are suppressed mainly by inertia of the bulk glass and to a lesser extent specific interactions at the protein-solvent interface. Thus, the inertia of the glassy matrix may be an influential factor in the determination of pharmaceutically relevant formulations.