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N α-Methylated phenylhistamines exhibit affinity to the hH4R—a pharmacological and molecular modelling study

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Abstract

Histamine H1-receptor agonists and antagonists exhibit affinity to the human histamine H4-receptor (hH4R). However, the pharmacological profiles between hH1R and hH4R exhibit similarities and differences. Since suprahistaprodifen and trifluoromethylphenylhistamine show significant affinity to hH4R, the aim of this study was to analyse a large number of new phenylhistamines, histaprodifens and phenoprodifens at hH4R to extend the pharmacological profile of these compound classes at hH4R. The hH4R-RGS19 fusion protein was co-expressed with Gαi2 and Gβ1γ2 in Sf9 insect cells, and [3H]histamine competition binding as well as GTPase assays were performed. Based on adequate crystal structures, homology models of hH4R 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 hH4R on molecular level. The exchange of the phenyl moiety of phenylhistamines into the diphenylpropyl moiety of histaprodifens acts, in contrast to hH1R, as partial agonism–inverse agonism switch at hH4R. Based on our studies, some phenylhistamine derivatives with significantly higher affinity at hH4R than at hH1R were identified. The molecular dynamic simulations revealed two different conformations for the highly conserved Trp6.48, 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 hH4R than at hH1R. Besides, we have identified partial agonism–inverse agonism switch between phenylhistamines and histaprodifens at hH4R. These results are very important to understand selectivity between hH1R and hH4R and to design new potent H1R and/or H4R receptor ligands.

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Abbreviations

cpd:

Compound

h:

Human

H1R:

Histamine H1 receptor

H4R:

Histamine H4 receptor

n. d.:

Not determined

TM:

Transmembrane Domain

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Acknowledgements

We thank A. Seefeld for performing the GTPase assays, A. Rossi and R. Winkler for performing the [3H]histamine binding assays and G. Wilberg for her competent help with the cell culture. We thank B. Striegl and M. Kunze for providing the compounds 3, 5, 7, 10–30. We thank Prof. Schlossmann for providing infrastructure for a part of experimental studies. This work was supported by DFG (STR 1125/1-1) of the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany

    Hans-Joachim Wittmann

  2. Department of Pharmaceutical/Medicinal Chemistry I, School of Pharmacy, University of Regensburg, 93040, Regensburg, Germany

    Sigurd Elz

  3. Institute of Pharmacology, Medical School of Hannover, 30625, Hannover, Germany

    Roland Seifert

  4. Department of Pharmaceutical/Medicinal Chemistry II, School of Pharmacy, University of Regensburg, 93040, Regensburg, Germany

    Andrea Straßer

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  1. Hans-Joachim Wittmann
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  2. Sigurd Elz
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  3. Roland Seifert
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  4. Andrea Straßer
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Corresponding author

Correspondence to Andrea Straßer.

Additional information

We dedicate this paper to the late Prof. Dr. Dr. Dr. h.c. Walter Schunack who developed phenylhistamines and histaprodifens.

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Wittmann, HJ., Elz, S., Seifert, R. et al. N α-Methylated phenylhistamines exhibit affinity to the hH4R—a pharmacological and molecular modelling study. Naunyn-Schmiedeberg's Arch Pharmacol 384, 287–299 (2011). https://doi.org/10.1007/s00210-011-0671-5

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