title: Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives.
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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Herman D
authors.initials: HD
authors.lastname: Lim
authors.forename: Bart
authors.initials: B
authors.lastname: Stegink
authors.forename: Remko A
authors.initials: RA
authors.lastname: Bakker
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D011968:Receptors, Histamine / Q000737:chemistry / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D001569:Benzodiazepines