Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H₁-Receptor Antagonists

• Uesawa Yoshihiro

  Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Japan

• Hishinuma Shigeru

  Department of Pharmacodynamics, Meiji Pharmaceutical University, Japan

• Shoji Masaru

  Department of Pharmacodynamics, Meiji Pharmaceutical University, Japan

書誌事項

タイトル別名

• Molecular Determinants Responsible for Sedative and Non-sedative Properties of Histamine H₁–Receptor Antagonists

抄録

There is argument whether non-sedative properties of histamine H₁–receptor antagonists (antihistamines) are determined by their active extrusions from the brain via P-glycoprotein or their restricted penetration through the blood-brain barrier. We have reported that sedative and non-sedative antihistamines can be well discriminated by measuring changes in their binding to H₁ receptors upon receptor internalization in intact cells, which depends on their membrane-penetrating ability. In this study, molecular determinants responsible for sedative and non-sedative properties of antihistamines were evaluated by quantitative structure-activity relationship (QSAR) analyses. Multiple regression analyses were applied to construct a QSAR model, taking internalization-mediated changes in the binding of antihistamines as objective variables and their structural descriptors as explanatory variables. The multiple regression model was successfully constructed with two explanatory variables, i.e., lipophilicity of the compounds at physiological pH (logD) and mean information content on the distance degree equality (IDDE) (r² = 0.753). The constructed model discriminated between sedative and non-sedative antihistamines with 94% accuracy for external validation. These results suggest that logD and IDDE concerning lipophilicity and molecular shapes of compounds, respectively, predominantly determine the membrane-penetrating ability of antihistamines for their side effects on the central nervous system.

収録刊行物

• Journal of Pharmacological Sciences

  Journal of Pharmacological Sciences 124 (2), 160-168, 2014

  公益社団法人 日本薬理学会

キーワード

• histamine H₁ receptor
• antihistamine
• sedation
• membrane penetration
• P-glycoprotein

詳細情報

• CRID: 1390001205179151488
• NII論文ID: 130003391480
• NII書誌ID: AA11806667
• DOI: 10.1254/jphs.13169fp
• COI: 1:CAS:528:DC%2BC2cXkt1egt74%3D
• ISSN: 13478648
• ISSN: 13478613
• NDL書誌ID: 025296131
• PubMed: 24476926
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I025296131
• Web Site: https://www.jstage.jst.go.jp/article/jphs/124/2/124_13169FP/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2014299888
• 本文言語コード: en
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