Wittmann, Hans-Joachim and Elz, Sigurd and Seifert, Roland and Strasser, Andrea (2011) N (alpha)-Methylated phenylhistamines exhibit affinity to the hH(4)R-a pharmacological and molecular modelling study. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 384 (3). pp. 287-299. ISSN 0028-1298, 1432-1912
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Histamine H-1-receptor agonists and antagonists exhibit affinity to the human histamine H-4-receptor (hH(4)R). However, the pharmacological profiles between hH(1)R and hH(4)R exhibit similarities and differences. Since suprahistaprodifen and trifluoromethylphenylhistamine show significant affinity to hH(4)R, the aim of this study was to analyse a large number of new phenylhistamines, histaprodifens and phenoprodifens at hH(4)R to extend the pharmacological profile of these compound classes at hH(4)R. The hH(4)R-RGS19 fusion protein was co-expressed with G(alpha i2) and G(beta 1 gamma 2) in Sf9 insect cells, and [H-3]histamine competition binding as well as GTPase assays were performed. Based on adequate crystal structures, homology models of hH(4)R were generated. Molecular modelling studies, including molecular dynamics and prediction of Gibbs energy of ligand binding, were performed in order to explain the pharmacological data at hH(4)R on molecular level. The exchange of the phenyl moiety of phenylhistamines into the diphenylpropyl moiety of histaprodifens acts, in contrast to hH(1)R, as partial agonism-inverse agonism switch at hH(4)R. Based on our studies, some phenylhistamine derivatives with significantly higher affinity at hH(4)R than at hH(1)R were identified. The molecular dynamic simulations revealed two different conformations for the highly conserved Trp(6.48), suggested to be involved in receptor activation. Furthermore, the predicted Gibbs energy of ligand binding for six selected phenylhistamines was in very good agreement with the experimentally determined affinities. We identified phenylhistamine derivatives with higher affinity at hH(4)R than at hH(1)R. Besides, we have identified partial agonism-inverse agonism switch between phenylhistamines and histaprodifens at hH(4)R. These results are very important to understand selectivity between hH(1)R and hH(4)R and to design new potent H1R and/or H4R receptor ligands.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTAMINE H-4 RECEPTOR; 2ND EXTRACELLULAR LOOP; IN-VITRO EVALUATION; 1ST POTENT; H-1-RECEPTOR; BENZIMIDAZOLE; AGONIST; INDOLE; H-2-RECEPTOR; ANTAGONIST; Histamine H-1 receptor; Histamine H-4 receptor; Gibbs energy; Phenylhistamines; Histaprodifens |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Jun 2020 07:49 |
| Last Modified: | 02 Jun 2020 07:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20357 |
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