Wagner, Eva and Wittmann, Hans-Joachim and Elz, Sigurd and Strasser, Andrea (2014) Pharmacological profile of astemizole-derived compounds at the histamine H-1 and H-4 receptor-H-1/H-4 receptor selectivity. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 387 (3). pp. 235-250. ISSN 0028-1298, 1432-1912
Full text not available from this repository. (Request a copy)Abstract
Astemizole, a H1R antagonist shows high affinity to the histamine H-1 receptor but only a moderate affinity to the histamine H-4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H-1 receptor and to increase affinity to the histamine H-4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H-1 and H-4 receptors. The new compounds show affinity to the histamine H-1 receptor in the pK (i) range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H-4 receptor was surprisingly rather low (pK (i) from 4.4 to 5.6). Three representative compounds were docked into the histamine H-1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H-4 receptor, a H-1/H-4-pharmacophore hypothesis was developed.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SITE-DIRECTED MUTAGENESIS; INTERNATIONAL UNION; AGONIST BINDING; MUTATIONAL ANALYSIS; MOLECULAR-CLONING; HIGH-AFFINITY; N-TERMINUS; ANTAGONIST; PROTEIN; CLASSIFICATION; Histamine H-1 receptor; Histamine H-4 receptor; Astemizole; JNJ7777120; Dual H1R/H4R ligands; Molecular dynamics |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Nov 2019 14:29 |
| Last Modified: | 18 Nov 2019 14:29 |
| URI: | https://pred.uni-regensburg.de/id/eprint/10619 |
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