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Molecular Determinants of Selective Agonist and Antagonist Binding to the Histamine H4 Receptor

[ Vol. 11 , Issue. 6 ]

Author(s):

Enade P. Istyastono, Chris de Graaf, Iwan J.P. de Esch and Rob Leurs   Pages 661 - 679 ( 19 )

Abstract:


The deorphanization of the histamine H4 receptor (H4R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H1, H2 and H3 receptor ligands were found to have significant affinity for H4R, several agonists and antagonists with high affinity for H4R and selectivity over the other histamine receptors were successfully designed and synthesized. Moreover, site-directed mutation studies on H4R have been performed and reveal detailed information on receptor-ligand interactions. This review will focus on the most important H4R ligand scaffolds and their structure-activity relationships and selectivity over other histamine receptors and specific H4R functional activity. Experimental data are used to construct and validate high resolution three-dimensional receptor-ligand models and, vice versa, in silico models are used to design and rationalize experimental studies to probe receptor-ligand interactions.

Keywords:

Histamine H4, structure-activity relationships, site-directed mutations, receptor-ligand interactions, Isothioureas, quinoxaline fragment, compound 52, histamine-analogues, probe, Affinity, chemogenomical analyses, SAR studies

Affiliation:

Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, VU University Amsterdam,De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.



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