Chemical & pharmaceutical bulletin最新文献_第3页

Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism. δ-阿片受体（DOR）选择性激动剂knt -127的结构-信号关系——第一部分：Morphinan骨架对g蛋白偏倚DOR激动作用的影响

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c25-00012

Keita Kajino, Tomoya Sugai, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Tomoya Kakumoto, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Asuka Inoue, Tsuyoshi Saitoh

{"title":"Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part I: Impact of the Morphinan Skeleton on the G-Protein-Biased DOR Agonism.","authors":"Keita Kajino, Tomoya Sugai, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Tomoya Kakumoto, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Asuka Inoue, Tsuyoshi Saitoh","doi":"10.1248/cpb.c25-00012","DOIUrl":"https://doi.org/10.1248/cpb.c25-00012","url":null,"abstract":"The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared to the μ-opioid receptor (MOR), which is commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, a DOR-selective agonist with a morphinan skeleton, offers analgesic and antidepressant benefits without inducing convulsions at therapeutic doses, unlike the conventional DOR agonist SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, a signaling pathway implicated in adverse opioid effects, the ligand structural basis for this biased signaling remains unclear. In this study, we explored the structure-signal relationships of KNT-127, focusing on its quinoline moiety, which is known to serve as an address domain responsible for DOR selectivity. Modifying the quinoline moiety by removing the aromatic rings reduced DOR selectivity and potency in relation to G-protein activation while diminishing both the potency and efficacy of β-arrestin recruitment. These results suggest that the morphinan skeleton is critical for reduced β-arrestin recruitment, while the quinoline moiety differentially modulates G-protein activation and β-arrestin recruitment. Together, our study expands the message-address concept, previously limited to receptor selectivity, by providing structural insights into the G-protein-biased agonism of DOR agonists, thereby guiding the design of safer DOR-targeting therapeutics.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"246-256"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Concise and Highly Stereoselective Synthesis of β,β-Disubstituted α,β-Unsaturated Esters. 简洁、高立体选择性合成β，β-二取代α，β-不饱和酯。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00751

Minoru Ozeki, Mizuki Tsuda, Serina Yamanouchi, Momoe Yamakawa, Kanako Fukuda, Hirotaka Sasa, Takuya Matsumoto, Aya Niki, Maaya Nobata, Takashi Shigeta, Tetsuya Kajimoto, Kenji Arimitsu, Shinzo Hosoi, Hiroki Iwasaki, Naoto Kojima, Ikuo Kawasaki

引用次数: 0

Effects of Shape on the Disintegration Time and Friability of Sucroferric Oxyhydroxide-Containing Mini-Tablets. 形状对含氢氧化铁迷你片崩解时间及脆度的影响。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00675

Hiroaki Omori, Homare Kurashima, Nobuyuki Isshiki, Yasuharu Kashiwagura, Shinya Uchida

{"title":"Effects of Shape on the Disintegration Time and Friability of Sucroferric Oxyhydroxide-Containing Mini-Tablets.","authors":"Hiroaki Omori, Homare Kurashima, Nobuyuki Isshiki, Yasuharu Kashiwagura, Shinya Uchida","doi":"10.1248/cpb.c24-00675","DOIUrl":"https://doi.org/10.1248/cpb.c24-00675","url":null,"abstract":"Sucroferric oxyhydroxide is a phosphate binder for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. This study aimed to determine the effects of tablet size, shape, and tensile strength on disintegration time and friability of sucroferric oxyhydroxide-containing mini-tablets. A linear relationship between the disintegration time and tensile strength was observed across all mini-tablets, except for those with smaller tablets (diameters: <1.8 mm). However, the relationship between friability and tensile strength was not significantly correlated under linear or exponential approximations. Explaining friability solely based on tensile strength was challenging, indicating the role of tablet shape. To visualize the effects of mini-tablet shapes and tensile strength on their disintegration time and friability, response aspects were analyzed. The response surface analysis revealed that the disintegration time was not affected by the tablet shape. The friability of the mini-tablets with a cup depth/diameter of 0.209 was lower (<0.2) than that of tablets with other cup depth/diameter across all tested ranges of tensile strength (1-6). A cup depth/diameter of 0.2 was identified as optimal for minimizing the friability of mini-tablets and can be implemented in commercial production without issues. In conclusion, tablet shape should be carefully considered during the development of mini-tablets to ensure low friability.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 3","pages":"257-263"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Characterization of 1-(Anthracen-9-ylmethyl)-1,5,9-triazacyclododecane (Ant-[12]aneN3) and Its DNA Photocleavage Activity. 1-（蒽-9-甲基）-1,5,9-三氮杂环十二烷（Ant-[12]aneN3）的设计、合成、表征及其DNA光裂解活性

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00705

Yoshimi Ichimaru, Koichi Kato, Yoshihiro Yamaguchi, Takayuki Sakamoto, Wanchun Jin, Masaaki Kurihara, Mikako Fujita, Masami Otsuka, Hiromasa Kurosaki

{"title":"Design, Synthesis, and Characterization of 1-(Anthracen-9-ylmethyl)-1,5,9-triazacyclododecane (Ant-[12]aneN3) and Its DNA Photocleavage Activity.","authors":"Yoshimi Ichimaru, Koichi Kato, Yoshihiro Yamaguchi, Takayuki Sakamoto, Wanchun Jin, Masaaki Kurihara, Mikako Fujita, Masami Otsuka, Hiromasa Kurosaki","doi":"10.1248/cpb.c24-00705","DOIUrl":"10.1248/cpb.c24-00705","url":null,"abstract":"Here, a DNA cleavage reagent (1-(anthracen-9-ylmethyl)-1,5,9-triazacyclododecane = Ant-[12]aneN3) was designed and synthesized, and its DNA photocleavage activity under UV irradiation at λ = 365 nm was evaluated. Ant-[12]aneN3 is a molecule containing anthracene as the photosensitizer and [12]aneN3 ( = 1,5,9-triazacyclododecane) as the DNA-interacting component. The cyclic polyamine [12]aneN3 could coordinate with zinc ions (ZnII) and affect DNA cleavage activity. Therefore, when Ant-[12]aneN3 reacted with Zn(NO3)‧6H2O, the product was not a ZnII complex but an N-protonated form of Ant-[12]aneN3. In DNA cleavage experiments with the pUC19 plasmid, Ant-[12]aneN3 also showed DNA photocleavage activity in a ZnII-independent manner. That is, [12]aneN3 enhances the DNA photocleavage activity of anthracene in a ZnII-independent manner, unlike bpa (bis(2-picolyl)amine), which was previously reported to enhance DNA cleavage activity by chelating ZnII. Under physiological conditions, the nitrogen atoms of [12]aneN3 appear protonated without the addition of ZnII salts and showed an affinity for the negatively charged DNA. The results of this study may facilitate the design of effective DNA cleavage reagents.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 2","pages":"103-107"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part II: Quinoline Ring Modifications for Enhanced G-Protein Signaling and Reduced β-Arrestin Recruitment. δ-阿片受体（DOR）选择性激动剂knt -127的结构-信号关系——第二部分：喹啉环修饰增强g蛋白信号传导和减少β-阻滞蛋白募集。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00796

Keita Kajino, Tomoya Sugai, Tomoya Kakumoto, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Takatsugu Hirokawa, Asuka Inoue, Tsuyoshi Saitoh

{"title":"Structure-Signal Relationships of the δ-Opioid-Receptor (DOR)-Selective Agonist KNT-127-Part II: Quinoline Ring Modifications for Enhanced G-Protein Signaling and Reduced β-Arrestin Recruitment.","authors":"Keita Kajino, Tomoya Sugai, Tomoya Kakumoto, Ryoji Kise, Riko Suzuki, Akihisa Tokuda, Yuki Sekiya, Risako Katamoto, Noriki Kutsumura, Yasuyuki Nagumo, Takatsugu Hirokawa, Asuka Inoue, Tsuyoshi Saitoh","doi":"10.1248/cpb.c24-00796","DOIUrl":"https://doi.org/10.1248/cpb.c24-00796","url":null,"abstract":"The δ-opioid receptor (DOR) continues to attract attention as a therapeutic target for the development of safer analgesics due to its ability to mediate pain relief with a lower risk of adverse effects compared to the μ-opioid receptor (MOR). Building upon our previous findings on KNT-127, a DOR-selective agonist with a morphinan scaffold, this study further explores the structure-signal relationships between quinoline ring modifications and the signaling bias toward Gi-protein activation while minimizing β-arrestin-2 recruitment. Our findings highlight the critical role of the 5'-position in modulating signaling bias. Bulky hydrophobic substituents, such as isopropoxy and cyclohexanoxy groups, effectively reduce β-arrestin-2 recruitment without compromising DOR binding affinity or Gi-protein activation. Molecular-docking and molecular dynamics simulations provided mechanistic insights, showing that these modifications change ligand interactions with the V2816.55-W2846.58-L3007.35 sub-pocket, thus selectively favoring Gi-protein signaling. These insights clarify the key interactions for the signaling bias in DOR agonists, offering a new framework for the design of DOR-targeted therapies with an improved therapeutic profile.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 4","pages":"336-348"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prediction of Intra-individual Variability in Bioequivalence Studies of 278 Formulations: Comprehensive Analysis Using Physicochemical and Pharmacokinetic Parameters. 278种制剂生物等效性研究的个体差异性预测：使用物理化学和药代动力学参数的综合分析。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00806

Masaki Higashino

{"title":"Prediction of Intra-individual Variability in Bioequivalence Studies of 278 Formulations: Comprehensive Analysis Using Physicochemical and Pharmacokinetic Parameters.","authors":"Masaki Higashino","doi":"10.1248/cpb.c24-00806","DOIUrl":"https://doi.org/10.1248/cpb.c24-00806","url":null,"abstract":"The purpose of the present study was to predict the intra-individual variability (%CVintra) values of Cmax using observed parameters of physicochemical and pharmacokinetic for a variety of formulations. A database was used to summarize the parameters of clinical bioequivalence (BE) studies of oral drugs, including the highest dose tablets, orally disintegrating tablets (ODT), and capsules (278 formulations [238 compounds]). As explanatory variables, %CVintra, inter-individual variability (%CVinter), absolute bioavailability (BA), Tmax, t1/2, dose number (Do), and dissolution rate (D%) were selected. Explanatory variables correlated with %CVintra were identified by multivariate analysis and grouped quantitatively by K-means clustering analysis. The %CVintra predictions compared three models of multiple regression, boosting tree, and neural network. In the neural network, the coefficient of determination (R2) and the root mean square error (RMSE) were the best, with good correlation between the predicted and observed values of the test data (R2 = 0.69). The explanatory variables used in this study are readily available from the literature of reference formulation and in vitro measurement. Therefore, predicting %CVintra for Cmax without conducting pilot studies is useful for clinical planning in the early stages of generic drug development. We believe that we could further contribute to speeding up and reducing the cost of generic drug development.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 4","pages":"349-354"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New Nucleoside Derivatives for Hybridization-Assisted Catalysis of Site-Selective Acetylation of 2'-OH of RNA. 杂交辅助催化RNA 2'-OH位点选择性乙酰化的新核苷衍生物。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c25-00068

Hayate Takasaki, Kentaro Kitazaki, Yurie Hadano, Hirotaka Murase, Jeongsu Lee, Yosuke Taniguchi, Shigeki Sasaki

引用次数: 0

Effect of Particle Size of Powdered Cellulose Nanofibers as an Additive in the Production of Orally Disintegrating Mini-Tablets by Direct Powder Compression. 粉末纤维素纳米纤维粒径对直接粉末压缩生产口腔崩解小片的影响。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c25-00042

Shohei Nakamura, Maya Shimasaki-Suzuki, Momoka Hamaoka, Ayumi Sakurada, Shinji Akiyama, Takatoshi Sakamoto

{"title":"Effect of Particle Size of Powdered Cellulose Nanofibers as an Additive in the Production of Orally Disintegrating Mini-Tablets by Direct Powder Compression.","authors":"Shohei Nakamura, Maya Shimasaki-Suzuki, Momoka Hamaoka, Ayumi Sakurada, Shinji Akiyama, Takatoshi Sakamoto","doi":"10.1248/cpb.c25-00042","DOIUrl":"https://doi.org/10.1248/cpb.c25-00042","url":null,"abstract":"Mini-tablets (MTs) allow for dosage adjustments according to children's weight and age. However, it is difficult to manufacture MTs with robust physical properties, and various formulation techniques are required. Adding cellulose nanofiber (CNF), a highly functional biomass material, to MTs improved the hardness and disintegration; however, the large variation in the weight and drug content of the resulting MTs remained a challenge. Therefore, this study analyzed the physical properties of CNF-containing MTs of different particle sizes and evaluated the effect of the particle size on MT manufacturing. CNF300, with an average particle size of approximately 300 µm, was pulverized to prepare CNF100, averaging 100 µm. The formulation included CNF (10, 30, and 50%), lactose hydrate, paracetamol, and magnesium stearate. The pharmaceutical powders mixed were loaded into a rotary tablet press equipped with a 3-mm multiple-tip tooling and compressed at 2, 5, and 8 kN forces. CNF100-containing MTs were manufactured via direct powder compression, and they showed lower variations in weight and drug content than those containing CNF300. The tensile strength of MTs containing CNF100 was smaller than that of those containing CNF300; however, a strength of ≥1 MPa (corresponding to ≥30 N hardness of a regular tablet) was obtained by setting the compression force to ≥5 kN. The MTs containing 30% CNF100 disintegrated in ≤30 s, regardless of the compression force. Thus, using smaller CNF particle sizes enabled the manufacturing of an orally disintegrating MT with adequate hardness and disintegration properties while also minimizing variations in MT weight and drug content.","PeriodicalId":9773,"journal":{"name":"Chemical & pharmaceutical bulletin","volume":"73 5","pages":"467-477"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Two New Halimanes with a γ-Lactone from Croton argyratus. 含γ-内酯的两个新哈利曼类化合物。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00734

Kanami Watanabe, Yohei Saito, Shuichi Fukuyoshi, Katsunori Miyake, David J Newman, Barry R O'Keefe, Kuo-Hsiung Lee, Kyoko Nakagawa-Goto

引用次数: 0

Bioinspired Total Synthesis of Polycyclic Natural Products. 多环天然产物的生物启发全合成。

IF 1.5 4区医学

Chemical & pharmaceutical bulletin Pub Date : 2025-01-01 DOI: 10.1248/cpb.c24-00843

Hayato Ishikawa

引用次数: 0