Fragment Based Design of New H 4 Receptor-Ligands with Anti-inflammatory Properties in Vivo

Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H 4 R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline (3) was identified as a new lead structure for H 4 R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4 R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant antiinflammatory properties in the carrageenan-induced paw-edema model

Effect of histamine H4 receptor ligands on cholinergic neurotransmission of the rat duodenum

The recently cloned histamine H4 receptor (H4R) was found to play a role in inflammatory and immune responses. Recently, immunohistochemical data have provided evidence that the H4R is also expressed in myenteric neurons of the rodent gastrointestinal tract, suggesting a role for this receptor in the regulation of intestinal peristalsis (1). In the present study we examined whether H4Rs have a role in the regulation of intestinal neurotransmission, by testing selective H4R ligands in the isolated rat duodenum. Twitch responses of longitudinal muscle strips to electrical field stimulation were abolished by atropine (1 µM) and partially reduced by hexamethonium (10 µM), suggesting that pre- and postganglionic cholinergic neurons were activated. Under these experimental conditions, the H4R agonist VUF8430 (2) and histamine, in the presence of H1-, H2- and H3-receptor blockade, did not change electrically-evoked contractions. Similarly ineffective were the selective H4R antagonists VUF10148 and VUF10214 (3), when tested at 10 nM and 100 nM. At higher concentrations (1-10 µM), these compounds evoked a dose-dependent inhibition of electrically evoked contractions, which, however, was mimicked by VUF10181, a chemically related analog, endowed with a 1000-fold lower affinity at H4R (3). In conclusion, functional experiments on isolated rat duodenum did not unravel any role of H4Rs in the control of intestinal neurotransmission. (1) Chazot, PL et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.27 (2) Lim, HD et al J Med Chem 2006;49:6650-6651 (3) Coruzzi, G et al. XXXVI EHRS Meeting, Florence, May 9-12th 2007, p.10

Differential effects of functionally different histamine H4 receptor ligands on acute irritant dermatitis in mice

The anti-inflammatory effects of histamine H4 receptor (H4R) antagonists opened new therapeutic options for the treatment of inflammatory/allergic diseases, but the role of H4R in inflammation is far from being solved. Aim of the present study was to investigate the role of structurally related H4R ligands of the aminopyrimidine class with different efficacies and functionalities (neutral antagonist ST-994, partial agonist ST-1006, inverse agonist ST-1012, and partial inverse agonist ST-1124) on croton oil-induced ear edema and pruritus in mice. The H4R ligands were administered subcutaneously before topical application of croton oil. While ST-1006 and ST-1124 were ineffective at any dose tested (10-100 mg/kg), both ST-994 and ST-1012 (30 and 100 mg/kg) significantly reduced croton oil-induced ear edema. Moreover, ST-994, ST-1006, and ST-1124, but not ST-1012, significantly inhibited croton oil-induced ear pruritus at 30 mg/kg. In accordance with results obtained with the reference H4R antagonist JNJ7777120 (100 mg/kg), histological examination of inflamed ear tissue indicated that treatment with ST-994 (30 mg/kg) led to a significant reduction in the inflammatory severity score and in the number of eosinophils infiltrating the tissue, while the number of degranulated mast cells in inflamed tissues was increased in comparison with the number of intact mast cells. These data indicate that croton oil-induced ear inflammation and pruritus seem to be clearly, but variably, affected by the H4R ligands tested. The potential advantage of dual effect of the H4R neutral antagonist ST-994 has to be carefully considered as a new therapeutic approach to the treatment of inflammatory diseases

Cannabinoid CB1 receptors are involved in the regulation of rat gastric acid secretion

The effects of cannabinoid CB1 receptor activation (HU-210) and blockade (SR141716A) on gastric acid secretion were determined in anaesthetized rats with lumen perfused stomach. The selective CB1-receptor agonist HU-210 (0.01-0-1 mg kg−1, i.v.) did not affect basal acid secretion while causing inhibition (maximum reduction 74%) of the gastric acid secretion stimulated by pentagastrin (10μ kg−1, i.v.). The inhibitory effect of HU-210 was reversed by the selective cannabinoid CB1-receptor antagonist SR141716A (1 mg kg−1, i.v.), but not by the selective CB2-receptor antagonist SR144528 (1 mg kg−1, i.v.). These results suggest that cannabinoid CB1 receptors may mediate inhibitory effects on gastric acid secretion in the rat