Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Volume 65, Issue 11
Displaying 1-15 of 15 articles from this issue
Communications to the Editor
Regular Articles
  • Lili Li, Ning Wang, Qizhong Jin, Qian Wu, Yafang Liu, Yan Wang
    2017 Volume 65 Issue 11 Pages 1004-1010
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Tong-Qiao-Huo-Xue Decoction (TQHXD) is a classical prescription in traditional Chinese medicine treating blood stagnation in the head and facial channels, especially cerebral ischemia. We investigate the effect of TQHXD on the expressions of related proteins of the blood–brain barrier (BBB) and analysis of constituents in the cerebrospinal fluid (CSF) on cerebral ischemic model rats. Here, we demonstrate that TQHXD protected the hippocampus neurons, reduced the opening of tight junction (TJ) and decreased the permeability of BBB by up-regulating ZO-1, occludin, claudin-5 expressions, down-regulating aquaporin-4 (AQP-4) and matrix metalloproteinase-9 (MMP-9) expressions. Meanwhile, we detected Muscone, ligustilide and hydroxysafflor yellow A in CSF on cerebral ischemic model rats. These compounds could be identified as the main active ingredients of TQHXD on protecting the damaged BBB. These results suggest that TQHXD could act as a potential neuroprotective agent against BBB damage for cerebral ischemia.

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  • Qian Wei, Guang Ta, Wenjing He, Wei Wang, Qiucheng Wu
    2017 Volume 65 Issue 11 Pages 1011-1019
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Chinese herbal medicine (CHM) has been used for treating insomnia for centuries. The most used CHM for insomnia was Polygonum multiflorum. However, the molecular mechanism for CHM preventing insomnia is unknown. Stilbene glucoside (THSG), an important active component of P. multiflorum, may play an important role for treating insomnia. To test the hypothesis, Kunming mice were treated with different dosages of THSG. To examine the sleep duration, a computer-controlled sleep-wake detection system was implemented. Electroencephalogram (EEG) and electromyogram (EMG) electrodes were implanted to determine sleep-wake state. RT-PCR and Western blot was used to measure the levels of lactate dehydrogenase (LDH) and saliva alpha amylase. Spearman’s rank correlation coefficient was used to identify the strength of correlation between the variables. The results showed that THSG significantly prolonged the sleep time of the mice (p<0.01). THSG changed sleep profile by reducing wake and rapid eye movement (REM) period, and increasing non-REM period. RT-PCR and Western blot analysis showed that THSG could down-regulate the levels of LDH and saliva alpha amylase (p<0.05). The level of lactate and glucose was positively related with the activity of LDH and saliva alpha amylase (p<0.05), respectively. On the other hand, the activities of LDH and amylase were negatively associated with sleep duration (p<0.05). The levels of lactate and glucose affect sleep homeostasis. Thus, THSG may prevent insomnia by regulating sleep duration via LDH and salivary alpha amylase.

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  • Koichi Takao, Kazuhiro Toda, Takayuki Saito, Yoshiaki Sugita
    2017 Volume 65 Issue 11 Pages 1020-1027
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    A series of cinnamic acid derivatives, amides (112) and esters (1322), were synthesized, and structure–activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 110, 1218, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 911, 15, 1722 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer’s disease.

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  • Koji Yamamoto, Taisuke Tamura, Yasuo Yoshihashi, Katsuhide Terada, Ets ...
    2017 Volume 65 Issue 11 Pages 1028-1034
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This study examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness. These effects were examined in terms of surface free energy and dispersibility. Dissolution, disintegration, and hardness were evaluated for tablets manufactured from powder mixtures of each MgSt hydrate form and other components, including ethenzamide as an active ingredient, using different mixing times. The surface energy was evaluated for MgSt mono- or dihydrate powder mixtures with a surface tensiometer. For dispersibility, the adhesion states of MgSt hydrates to other components were visually observed via near-infrared (NIR) chemical imaging. The dispersion behavior of MgSt hydrates was examined by quantitative evaluation of skewness and kurtosis of histograms, based on NIR images, and domain size estimated from their binary images. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR chemical imaging is a useful methodology for improving the understanding of tablet manufacturing blending processes.

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    Editor's pick

    Magnesium stearate (MgSt), an essential lubricant in the manufacturing of tablets, is available in several hydrate forms with different qualities that affect the physical properties of tablets. This article examined MgSt mono- and dihydrates, and their effects on tablet dissolution, disintegration, and hardness were examined in terms of surface free energy and dispersibility. It was found that changes in those parameters related to dispersibility and dissolution differed between MgSt hydrates. This suggests that the quantitative determination of dispersibility of MgSt using NIR-CI is a useful methodology for improving the understanding of tablet manufacturing blending processes.

  • Yukari Kakino, Yoshihiro Hishikawa, Risako Onodera, Kohei Tahara, Hiro ...
    2017 Volume 65 Issue 11 Pages 1035-1044
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Jellies for oral administration are dosage forms that contain water, as stipulated in the Japanese Pharmacopeia, and heat is generally applied to the jellies during the manufacturing process. Therefore, it is difficult to formulate drugs that may be affected adversely by water and/or heat. To solve this problem, we tried to develop a powder form of gel as a novel dosage form (dry jelly: jelly medicine extemporaneously prepared) that is converted to jelly after addition of water at the time of administration. For this purpose, a basic gel formulation consisting of pectin, glucono-δ-lactone, dibasic calcium phosphate hydrate, and sucrose was investigated to evaluate the critical factors affecting gelation phenomena. The gel form was developed by adjusting the amount of each component of the formulation and of water added. Gelation occurred even with hard water containing metal ions (hardness of approximately 304 mg/L), and no changes in gel hardness occurred. The desired gel hardness could be controlled by adjusting the amount of water. The gel hardness changed over time after the addition of water, but this change did not affect the dissolution behavior of drugs formulated in the dry jelly.

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    Editor's pick

    Jellies for oral administration are dosage forms that contain water and heat is generally applied to the jellies during the manufacturing process. Therefore, it is difficult to formulate drugs that may be affected adversely by water and/or heat. To solve this problem, the authors develop a powder form of gel as a novel dosage form (dry jelly) that is converted to gel after addition of water at the time of administration. The concept of dry jelly gelation by water addition is shown in graphical abstract. In the article, the critical factors affecting gelation phenomena as well as physical and drug dissolution properties of the gel prepared from drug-containing dry jelly are evaluated.


  • Sakura Yoshida, Kaori Koga, Miho Iwataka, Takeshi Fuchigami, Mamoru Ha ...
    2017 Volume 65 Issue 11 Pages 1045-1050
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Supplementary material

    Selenium is an essential trace element for humans and animals. Fish and shellfish are known to be rich in selenium and suppose to be an effective selenium source. In this study, we characterized the selenium species in the Shijimi clam (Corbicula japonica), which is a typical clam eaten in Japan. The Shijimi clam contains a relatively high concentration of selenium (3.5 µg-selenium/g-dry Shijimi). Approximately 30% of the total selenium in the Shijimi clam meat was extractable with water, while selenium in the Shijimi clam was hardly extracted with ethanol, chloroform and hexane. Based on an ultrafiltration study, the molecular mass of the major selenium species in the Shijimi water-extract was estimated to be less than 5000. Because amphoteric selenium species were contained in the Shijimi water-extract, which was indicated by ion-exchange chromatographic separation, an ion-pair reagent was utilized to extract the ionic selenium species into an organic solvent. A matrix assisted laser desorption ionization (MALDI) time of flight (TOF)-mass spectrometric analysis revealed the selenium isotopic pattern involving one selenium atom in a molecule with the 80Se molecular ion peak at m/z 534. This selenium species was mainly found in the visceral part of the Shijimi clam by imaging mass spectrometry.

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  • Shuichi Mori, Ryohei Takagaki, Shinya Fujii, Ko Urushibara, Aya Tanata ...
    2017 Volume 65 Issue 11 Pages 1051-1057
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    The progesterone receptor (PR) controls various physiological processes, including the female reproductive system, and nonsteroidal PR ligands are considered to be drug candidates for treatment of various diseases without significant adverse effects. Here, we designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.

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    Editor's pick

    The authors designed and synthesized m-carborane-based secondary alcohols and investigated their PR-ligand activity. All the synthesized alcohols exhibited PR-antagonistic activity at subnanomolar concentration. Among them, alcohols having a small alkyl side chain and a 4-cyanophenyl group, such as 7a, also exhibited PR-agonistic activity in a relatively high concentration range. Optical resolution of secondary alcohols having a methyl side chain was performed, and the PR-ligand activity and PR-binding affinity of the purified enantiomers were examined. The chirality of the secondary alcohol appears to have a more significant influence on PR-agonistic activity than on antagonistic activity.

  • Satoshi Mikami, Masanori Kawasaki, Shuhei Ikeda, Nobuyuki Negoro, Shin ...
    2017 Volume 65 Issue 11 Pages 1058-1077
    Published: November 01, 2017
    Released on J-STAGE: November 01, 2017
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    Supplementary material

    It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3′,5′-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

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    Editor's pick

    This article describes the discovery of a new class of lead compound 5 by combining structural features from previously disclosed two chemotypes, represented by 3 and 4, and subsequent medicinal chemistry efforts to optimize potency, PDE selectivity, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts culminated in the identification of 20, which demonstrated significant elevation of cGMP levels in rat brains, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.

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