Simultaneous determination of YM928, a novel noncompetitive AMPA receptor antagonist, and its demethylated metabolite in rat, dog and monkey plasma by high-performance liquid chromatography with ultraviolet detection

A specific HPLC method for the simultaneous determination of YM928, a novel noncompetitive AMPA receptor antagonist, and its demethylated metabolite (YM-58875) in rat, dog and monkey plasma was developed and validated. The method utilized multiple-step liquid-liquid extraction followed by a reversed-phase HPLC with UV detection at 275 nm. No interfering peaks were observed at the retention times of YM928, YM-58875 or internal standard. The validated quantitation range was 5-5000 ng/mL for both YM928 and YM-58875 when 1 mL of the plasma sample was used. The intra- and inter-day precision was less than 5.3 and 2.5% for YM928, and 3.7 and 2.3% for YM-58875, respectively. The intra- and inter-day accuracies were -8.7-5.3% and 0.7-1.9% for YM928, and -10.0-6.1% and 1.3-3.4% for YM-58875, respectively. The mean recoveries in the extraction process were 52.7-62.8%. The utility of this analytical method was demonstrated by the investigation of the pharmacokinetics of the unchanged drug and its metabolite in preclinical studies.     

UNDERSTANDING STRUCTURAL EFFECTS OF MULTIPOLE MOMENTS ON AQUEOUS SOLVATION OF IONS USING THE SOFT-STICKY DIPOLE-QUADRUPOLE-OCTUPOLE WATER MODEL

The effects of water multipole moments on the aqueous solvation of ions were determined in Monte Carlo simulations using soft-sticky dipole-quadrupole-octupole (SSDQO) water. Water molecules formed linear hydrogen bonds to Cl(-) using the new SSDQO1 parameters, similar to multi-site models. However, the dipole vector was tilted rather than parallel to the oxygen-Na(+) internuclear vector as in most multi-site model, while experiment and ab initio molecular dynamics simulations generally indicate a range of values between tilted and parallel. By varying the multipoles in SSDQO, the octupole was found to determine the orientation around Na(+). Moreover, analysis of the multipoles of more conventional models is predictive of their performance as solvents.     

Correlation between Mössbauer isomer shifts and XPS binding energies

A series of low-spin pentacyanoferrates (‖) of the type Na₃[Fe-(CN)₅L] (L = phosphine or phosphite) have been characterized by⁵⁷Fe Mössbauer spectroscopy and X-ray photoelectron spectroscopy. The Fe?P bond in Na₃[Fe(CN)₅L] is discussed in terms of a correlation between the isomer shift and the binding energy. It has been demonstrated that the isomer shift increases with the decreasing Fe2p_3/2 binding energy. The Mössbauer isomer shift reflects the total electron density at the nuclear site, while the chemical shift in the binding energy is concerned with the electron density on the atom of interest. The increasing Fe-to-P back donation leads to an increase of the s-electron density at the iron nucleus, i.e. a decrease of the isomer shift. The increasing tendency in the Fe2p_3/7 binding energy is interpreted by the increasing Fe-to-P back donation.     

A Defect‐Free Ring Polymer: Size‐Controlled Cyclic Poly(tetrahydrofuran) Consisting Exclusively of the Monomer Unit

A series of size‐controlled, cyclic poly(tetrahydrofuran)s ( of 4 400–8 600) that consist exclusively of the monomer, i.e., oxytetramethylene, unit ( I ) have been prepared in high yield through the metathesis polymer cyclization of a telechelic precursor having allyl groups, 1 , in the presence of a Grubbs catalyst, and the subsequent hydrogenation of the linking, i.e., 2‐butenoxy, unit in the presence of an Adams' catalyst (PtO₂). A remarkable topology effect has subsequently been observed upon the isothermal crystallization of these two model polymers, showing distinctive spherulite growth rates and spherulite morphologies in comparison with the relevant linear poly(tetrahydrofuran) counterpart that has ethoxy end groups ( II ).

     

Biochemical, molecular genetic, and structural analyses of the staphylococcal nucleoid.

The nucleoid structure of an important human pathogen, Staphylococcus aureus, was dissected by atomic force microscopy (AFM). The nucleoids dispersed on a cover glass consisted of fibrous units with two different widths of 40 and 80 nm, a feature shared with those of Escherichia coli. On the other hand, cells exposed to an oxidative stress exhibited clogged nucleoids. A knock-out of mrgA (metallo regulated genes A) encoding a staphylococcal homolog of the nucleoid compaction factor (E. coli Dps) eliminated the compaction response to the oxidative stress and reduced the susceptibilities to H2O2 and UV irradiation. We also observed that the negative supercoiling of plasmids is increased by the oxidative stress. A possible interrelation between the helical density and the nucleoid compaction is discussed in relation to the oxidative stress response.     

Transition state dynamics of N2O4 <==> 2NO2 in liquid state

Transition state dynamics of dissociation and association reactions N2O4 <==> 2NO2 in liquid state are studied by classical molecular dynamics simulations of reactive liquid NO(2) at 298 K. An OSPP+LJ potential between NO(2) molecules proposed in paper I [J. Chem. Phys. 115, 10852 (2001)], which takes into account the orientational sensitivity of the chemical bond, has been used in the simulation. The trajectory and energy evolution of various reactions are studied in the OSPP+LJ liquid, which reproduces both the observed liquid phase equilibrium constant and Raman band shape of the dissociation mode. It is found that a NO(2) pair in reactive liquid NO(2) is bound when E(T)<0 and dissociates when E(T)>0, and the dissociation of a reactant pair occurs when the transition state (TS) surface of E(T)=0 is crossed from negative to positive, where E(T) is the sum of the potential and kinetic energies of intermolecular motion of the pair. Two types of dissociation are found depending on the source of energy for dissociation; the first type D is the dissociation via collisional activation of the reactive mode by solvent molecules, and the second type T is the dissociation via bond transfer from a dimer to a monomer NO(2) through the TS of NO(2) trimer. It is concluded that the type T dissociation is found to be much more probable than the type D dissociation because of easy energy conservation. The reactant experiences the TS of NO(2) trimer for a long time (1-10 ps) in NO(2) mediated bond transfer reactions, and crossing and recrossing trajectories and dynamics in the TS neighborhood are studied.     

Synthetic studies on indoles and related compounds. XXXI. Chemical confirmation of the synthetic route for the benz[f]indole skeleton and its application

To confirm the structure of ethyl 9-methoxybenz[f]indole ( 8a ) prepared from ethyl pyrrole-2-carboxylate ( 4 ) via a new synthetic route, the following chemical correlation work was performed. Ethyl 9-methoxybenz[f]in-dole ( 8a ) was converted to 1-benzyl-3-methyl-5,6,7,8-tetrahydrobenz[f]indole ( 25 ), which was alternatively and authentically synthesized from ethyl 3-methylpyrrole-2-carboxylate ( 11 ). On the basis of the established route to the benz[f]indole nucleus, two representative benz[f]indoles, benz[f]indole ( 1 ) and 4,9-dioxobenz[f]indole ( 26 ) were synthesized.     

New synthetic equivalent of nitromalonaldehyde treatable in organic media

beta-Nitroenamines having a formyl group at the beta-position behave as the synthetic equivalent of unstable nitromalonaldehyde, which is a useful synthon for syntheses of versatile nitro compounds. High solubility of the nitroenamines into general organic solvents enables us to conduct reactions in the organic media accompanied by easy experimental manipulations and considerable safety. When nitroenamines are treated with 1,2-bifunctional nucleophiles such as hydrazines, hydroxylamine and glycine ester, nitrated pyrazoles, isoxazole and pyrrole-2-carboxylate were readily prepared. This methodology was also applicable to guanidines and 1,2-diamines, leading to pyrimidines and 1,4-diazepines, respectively.     

Psychological and Antibacterial Effects of Footbath Using the Lindera umbellata Essential Oil

Lindera umbellata (Lu) essential oil primarily contains linalool and has relaxation properties. We investigated the psychological and antibacterial effects of footbath with Lu essential oil. The participants included 20 women without medical history and received two intervention plans: footbath without any essential oil and footbath using Lu essential oil. Next, questionnaires regarding impressions and mood states were provided for them to answer. In addition, their autonomic nervous system activity was measured, and the aerobic viable of count on the feet was determined. The high-frequency value reflecting the parasympathetic nervous system activity significantly increased after footbath using Lu essential oil. In the questionnaire about the mood states, the subscale scores of tension–anxiety, depression, fatigue, and confusion after intervention were lower than those before intervention regardless of the use of the essential oil. Conversely, the anger–hostility score decreased only in the group using Lu essential oil. Furthermore, the decrease in aerobic viable count after intervention was not significantly different between the two groups. Footbath using Lu essential oil increased the parasympathetic nervous system activity and relieved anger. Taken together, we suggest that footbath using Lu essential oil has a relaxation effect.