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.

2,4-Diaminopyrimidines as histamine H4 receptor ligands—Scaffold optimization and pharmacological characterization

“…On the one hand, H 4 R binding in the low nanomolar concentration range has been reported for these compounds but, on the other hand, they show high structural similarity to H 3 R antagonists. 27 The atypical neuroleptic clozapine has become a lead in H 4 R research (pK i = 6.8) 28 despite exhibiting high affinities to multiple biogenic amine receptors. 29 It is thought that it mainly mediates its antipsychotic effects via dopamine D 2 -like receptors as well as serotonin 5-HT 2 receptor subtypes though clozapine exhibits substantial affinity for other biogenic amine receptors such as histamine H 1 and adrenergic a 1 receptors.…”

“…30 Optimized oxazepines possess improved H 4 R affinities and agonist efficacy while showing H 1 R antagonism. 28 A scaffold hopping approach resulted in quinazolin-4-amine VUF10497, which was reported as a dual acting H 1 R/H 4 R ligand (pK i = 7.7/8.2). 31 The combination of tricyclic structural elements and a methylpiperazine group can also be found in the patent literature 32 (e.g., compound 5), where its H 4 R affinity has been claimed.…”

CuBr/N,N‐Dimethylglycine‐Catalyzed Coupling Reaction of 2‐Chlorotrifluoroacetanilides with Phenols at Mild Conditions

“…Generally, both electron-rich and electron-deficient phenols were compatible with these reaction conditions, delivering the corresponding diaryl ethers with good to excellent yields (Entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Noteworthy is that some sterically hindered phenols, such as 2-substituted phenols and 2,4,6-trimethylphenol, also worked well to provide 3k-3n in about 70% yield (Entries 10-13).…”

A QSAR study on 2-(4-methylpiperazin-1-yl)quinoxalines as human histamine H4 receptor ligands

“…These analogues were synthesized on the basis of flexible alignment model of VUF6884 (a tricyclic clozapine analogue) and JNJ7777120 (an indole-N-methylpiperazine derivative). 20 The model suggested that both the compounds had overlapping binding mode for the H 4 receptor. The reported quinoxaline derivatives are having the hybrid scaffold based on the structures of clozapine analogue and indole anologue.…”