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Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives
- Source :
- Smits, R A, Lim, H D, Stegink, B, Bakker, R A, de Esch, I J P & Leurs, R 2006, ' Characterization of the histamine H4 receptor binding site. Part 1. Synthesis and pharmacological evaluation of dibenzodiazepine derivatives ', Journal of Medicinal Chemistry, vol. 49, no. 15, pp. 4512-6 . https://doi.org/10.1021/jm051008s, Journal of Medicinal Chemistry, 49(15), 4512-6. American Chemical Society
- Publication Year :
- 2006
- Publisher :
- American Chemical Society, 2006.
-
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.
- Subjects :
- Agonist
Models, Molecular
Stereochemistry
medicine.drug_class
Ligands
Cell Line
Receptors, G-Protein-Coupled
chemistry.chemical_compound
Benzodiazepines
Radioligand Assay
Structure-Activity Relationship
SDG 3 - Good Health and Well-being
Drug Discovery
Chlorocebus aethiops
medicine
Structure–activity relationship
Animals
Humans
Histamine H4 receptor
Binding site
JNJ-7777120
Receptors, Histamine H4
Binding Sites
Stereoisomerism
chemistry
Molecular Medicine
Receptors, Histamine
Oxazepine
Pharmacophore
Histamine
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 15204804 and 00222623
- Volume :
- 49
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....b9e46bbc5aa95a367ff4135d74a7ffac