Essential Structure of Opioid κ Receptor Agonist Nalfurafine for Binding to κ Receptor 1: Synthesis of Decahydroisoquinoline Derivatives and Their Pharmacologies

On the basis of the three-dimensional pharmacophore model of opioid κ agonists, we simplified the structure of nalfurafine (selective κ agonist) to find the essential structural moieties for binding the opioid receptors, especially κ receptor type. As a result, we found that the trans-fused decahydroisoquinoline derivatives without a phenol ring bound the opioid receptor in micromolar order and that both the amide side chain and the nitrogen substituted by the cyclopropylmethyl group were indispensable moieties for eliciting the κ selectivity. The simple decahydroisoquinoline without amide side chain also bound the opioid receptor without receptor type selectivity, suggesting that the message-address concept would be applicable to even these simple derivatives. These findings that the simple decahydroisoquinoline derivatives showed the affinities for the opioid receptors, especially some of the compounds showed κ selectivity, are the first example in the opioid field.     

Taste-masking effect of physical and organoleptic methods on peppermint-scented orally disintegrating tablet of famotidine based on suspension spray-coating method

Orally disintegrating tablets (ODTs) are useful for improving benefits for patients of various ages. Masking the unpleasant taste of a drug is an important factor in the compliance of patients who take ODTs. We evaluated the taste acceptability effects of various taste-masking methods on bitter famotidine ODTs as a clinical pharmacological study. The following methods were tested to compare taste-masking effects: physical masking by spray-coating famotidine with ethyl cellulose versus organoleptic masking with added sweetener and flavor. The ODT samples were prepared as single or combinations of each taste-masking method using a novel suspension spray-coating method including a placebo. A total of 31 healthy volunteers were enrolled in this randomized, double-blind study and asked to score their bitterness, sweetness and total palate impressions by 100?mm visual analogue scale (VAS). VAS scores were significantly improved by the physical and organoleptic methods as compared to without taste-masked ODTs. Furthermore, the combination of both taste-masking methods was most effective for improving palatability and VAS scores were similar to those of placebo ODTs. The results of this study suggest that different taste-masking mechanisms function cooperatively.     

A new application of statistical moment theory to evaluate the swelling behavior of thermo-responsive gels

The loosely cross-linked poly(acryloyl-L -proline methyl ester) gel, which is known as one of the typical thermo-responsive gels, shows a volume transition around approximately 14°C in pure water. This volume transition is shifted to higher temperature by treatment in aqueous sodium dodecyl sulfate (SDS). The analysis of the swelling-temperature curve (frequency distribution) was performed according to a moment analysis, in which the area under the swelling-temperature curve (AUC), mean swelling transition temperature (MSTT) and variance of swelling transition temperature (VSTT) were calculated. It is shown that the apparent volume transition temperature can be estimated from MSTT and that VSTT can be used to characterize the shape of the corresponding curves.     

Study of the thermal degradability of poly(α-methylstyrene) with modified end groups

To induce degradabilities in polymers in response to environmental conditions, endm odification reactions of poly(α-methylstyrene) (PMS) derivatives were carried out. 2-Phenylallyl halide derivatives such as 2-phenylallyl bromide, 2-(p-tolyl)allyl bromide, and α-trifluoromethylstyrene were found to be suitable end-modification agents. For example, the ω-2-phenylallyl-PMS derivative was prepared with almost quantitative functionality by the reaction of the living PMS derivative with 2-phenylallyl bromide. In a similar way, ω-3,3-difluoro-2-phenylallyl- and ω-2-(4-toly)allyl-PMS derivatives were synthesized. Based on thermogravimetric analysis, the onset of the degradation temperature of the endmodified PMS derivatives decreased in the following order: ω-hydrogen- > ω-3,3-difluoro-2-phenylallyl- > ω-2-phenylallyl- > ω-2-(p-tolyl)allyl-PMS. Actually, the onset temperature of ω-2-(p-tolyl)allyl-PMS derivatives was 50°C lower than that of ω-H-PMS derivatives. These results indicate that the active species is produced effectively at the endunsaturated bond, which initiates depolymerization of the polymer at rather low temperatures. Therefore, it is concluded that a 2-phenylallyl substituent at the end of the PMS chain induces effective degradation through a radical mechanism.     

A new algorithm for surface tension model in moving particle methods

A new algorithm for the surface tension model was developed for moving particle methods. The algorithm is based on the link‐list search algorithm and the continuum surface tension (CST) model. The developed algorithm with the CST model was implemented to a kind of moving particle approach, the finite volume particle (FVP) method. The FVP method with the new algorithm was tested by oscillatory behaviour of a two‐dimensional droplet. The oscillatory period agrees well with analytical one, and the transient shape of the droplet is also in good agreement with that obtained by other numerical methods. The droplet impact on a liquid surface was also studied using the new algorithm. The deposition and splashing phenomena were clearly reproduced. Simulated spread radius of the splashing phenomena was consistent with a power law. Copyright © 2007 John Wiley & Sons, Ltd.     

Preparation of cyclohepta and benzo[ef]cycl[3.2.2]azines

Some cyclohepta[ef]cycl[3.2.2]azines were prepared from cyclohepta[hi]indolizines and electron deficient acetylenes in the presence of appropriate oxidants. Also, benzo[ef]cycl[3.2.2]azines were obtained similarly in good yields.     

Pulse radiolysis study of formation of poly(4-vinylbiphenyl) anions in 2-methyltetrahydrofuran solution at 100–120 K

The reactions of poly(4-vinylbiphenyl) (denoted as PVB) polymers and biphenyl molecules with solvated electrons in the 2-methyltetrahydrofuran (MTHF) solvent have been studied at 100–120 K by electron-pulse radiolysis. The formation of PVB polymer anions as well as biphenyl anions was observed by the electron-pulse irradiation of the MTHF-PVB(or biphenyl) solution. The anions are formed by two processes; a rapid formation during the pulse irradiation (<20 ns) and a slow formation after the pulse irradiation. The slow formation is due to a diffusion-controlled reaction between solutes, such as PVB and biphenyl, and solvated electrons. It was found that the reaction efficiency, expressed in monomer unit, of PVB polymers is 1/27 of that of biphenyl molecules. The reaction radius for the electron capture reaction of PVB polymers is estimated as 200–370 A, which is much larger than the gyration radius (107 A) of polymer coils in MTHF solution.     

UV-Vis spectroscopic study on effects of pressure for adsorption ofp-nitrotoluene at liquid-solid interface

The behavior ofp-nitrotoluene adsorbed at zeolite/n-heptane interface has been investigated by the electronic spectroscopy under pressure up to 300 MPa. The uv-vis absorption bands of adsorbedp-nitrotoluene were deconvoluted into ones for the species adsorbed on the cation sites, and one for that on the pore wall of zeolite. The peak of adsorbed species on the cation site red-shifted by 20–80 nm from the position of the same species in the liquid phase, and their magnitudes of shift depended on the strength of electric field generated by the cation in zeolites. The peak intensities of adsorbed species on the cation site were enhanced but these or the pore wall site were reduced with the increase in pressure, suggesting that a part ofp-nitroluene molecules on the pore wall site desorbed and the adsorption on the cation site was enhanced by compression. The pressure dependence of peak intensity indicated that the behavior of this adsorption system was strongly governed by the solvation structure of the adsorbate in the zeolite pore. In particular, it was found that the adsorption of solvent molecules on the cation site strongly affected the volume change of the adsorption system.     

Improvement of Nitrogen Supply for L-Threonine Production by a Recombinant Strain of Serratia marcescens

Serratia marcescens T-2000 was previously reported to be an l-threonine-producing strain that harbors the recombinant plasmid carrying the mutant-type threonine operon. This strain produced 55 g of l-threonine/L of the medium containing urea as a nitrogen source after 72 h of cultivation. In the urea-containing medium, transitory stop of the growth was observed during the early period of cultivation when the entire amount of ammonium ion formed from urea via heat decomposition disappeared in the medium. This indicated that the shortage of ammonium supply in cells might delay both the cell growth and the l-threonine production. The use of ammonia water as a nitrogen source for l-threonine production was therefore studied, because microbial cells generally assimilate this source more readily than urea. When ammonia water was automatically fed to the medium so as to maintain the pH of the medium at around 7, the growth was accelerated, and the l-threonine production reached a maximum of 65 g/L at 48 h. Under these conditions, sucrose, a carbon source, was continuously fed to the medium, resulting in the production of 100 g of l-threonine/L at 96 h. Thus, the l-threonine productivity of the recombinant l-threonine-producing strain could be increased by devising the method for supply of a nitrogen source.     

Observation of magnetic multilayers by electron holography.

Magnetic structures of Co/Cu multilayers in cross section are observed by two kinds of electron holography: a Fourier method and a phase-shifting method, which is introduced briefly. The Fourier method can easily reconstruct wave functions and is applied to many specimens, whereas the phase-shifting method requires longer time for processing, but has a higher spatial resolution that permits us to discuss fine structures. Magnetization vectors in Co layers aligning parallel and separating into two blocks with antiparallel alignment are observed. Magnetic blurring on the boundary between Co and Cu in the reconstructed phase images is larger than the estimated atomic roughness.