Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives.
Article Details
- CitationCopy to clipboard
Smits RA, Lim HD, Stegink B, Bakker RA, de Esch IJ, Leurs R
Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives.
J Med Chem. 2006 Jul 27;49(15):4512-6.
- PubMed ID
- 16854056 [ View in PubMed]
- Abstract
A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H4 receptor (H4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine (7j), a potent H4R agonist (H4R, pKi = 7.6). Pharmacological data suggests that the series of nonimidazole compounds can be used to describe the orthosteric binding site of the H4R because both 2 and 7j displace [3H]histamine in a competitive manner. Furthermore, it is demonstrated that the effects of 7j are competitively antagonized by the selective H4R antagonist JNJ 7777120 (1), indicating considerable overlap of their binding sites. On the basis of the derived structure-activity relationships and additional pharmacological results, a pharmacophore model was constructed, which will be the premise for the design of novel H4R ligands.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Clozapine Histamine H4 receptor Protein Humans NoAntagonistDetails - Binding Properties
Drug Target Property Measurement pH Temperature (°C) Clozapine Histamine H4 receptor Kd (nM) 20.9 N/A N/A Details Clozapine Histamine H4 receptor Kd (nM) 14.5 N/A N/A Details Clozapine Histamine H4 receptor Kd (nM) 11.9 N/A N/A Details Clozapine Histamine H4 receptor Kd (nM) 70.2 N/A N/A Details