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523012 
Journal Article 
Characterization of the histamine H-4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives 
Smits, RA; Lim, HD; Stegink, B; Bakker, RA; de Esch, IJP; Leurs, R 
2006 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
49 
15 
4512-4516 
English 
A series of dibenzodiazepine derivatives was synthesized to probe the binding site of the recently discovered histamine H-4 receptor (H4R). Optimization of the lead structure clozapine (2) resulted in (E)-7-chloro-11-(4-methylpiperazin-l-yl) dibenzo[b, f][1,4] oxazepine (7j), a potent H4R agonist (H4R, pK(i) = 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 [H-3] 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. 
bone-marrow; cloning; potent; agonist; antagonists; clozapine; ligands