Molecular determinants responsible for sedative and non-sedative properties of histamine H₁-receptor antagonists.
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) (r(2) = 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.
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Japan.
Yoshihiro
Y
Uesawa
Shigeru
S
Hishinuma
Masaru
M
Shoji
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002463:Cell Membrane Permeability; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D011969:Receptors, Histamine H1 / Q000378:metabolism; D012044:Regression Analysis; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006634:Histamine H1 Antagonists; D039563:Histamine H1 Antagonists, Non-Sedating; D006993:Hypnotics and Sedatives; D011969:Receptors, Histamine H1