Molecular determinants of selective agonist and antagonist binding to the histamine H₄ receptor.
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.
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.
Enade P
EP
Istyastono
Chris
C
de Graaf
Iwan J P
IJ
de Esch
Rob
R
Leurs
D001665:Binding Sites / Q000187:drug effects; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011968:Receptors, Histamine / Q000737:chemistry; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4