VUF 10166

VUF10166 is a novel, potent and competitive antagonist for 5-HT3A receptor with K_i of 0.04 nM, its affinity at 5-HT3AB receptor is significantly lower.

Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole histamine H4 receptor agonist.[Pubmed:17154494]

J Med Chem. 2006 Nov 16;49(23):6650-1.

During an in-house database screen, we identified S-(2-guanidylethyl)-isothiourea as a high affinity agonist for the histamine H4 receptor, with a 33-fold selectivity over the histamine H3 receptor and negligible affinity for the other histamine receptor subtypes. This nonimidazole ligand is introduced as a useful and complementary pharmacological tool that enables further unraveling of the physiological roles of the H4 receptor.

Effects of a new antiallergic drug, VUF-K-8788, on infiltration of lung parenchyma by eosinophils in guinea pigs and eosinophil-adhesion to human umbilical vein endothelial cells (HUVEC).[Pubmed:11642316]

Biol Pharm Bull. 2001 Oct;24(10):1127-32.

Airway inflammation and reversible airway obstruction are hallmarks of bronchial asthma. In this study, we investigated the effects of a new antiallergic drug, 7-[3-[4-(2-quinolinylmethyl)-1-piperazinyl]-propoxy]-2,3-dihydro-4H-1,4-benzothia zin-3-one (VUF-K-8788), on histopathological changes in lung parenchyma of guinea pigs during late-phase asthmatic reaction (LAR), and on eosinophil-adhesion to human umbilical vein endothelial cells (HUVEC). Repeated exposure to ovalbumin of sensitized guinea pigs induced inflammatory phenomena such as hyperplasia of airway epithelial cells, perivascular edema and infiltration of lung parenchyma by eosinophils. VUF-K-8788 inhibited these histopathological phenomena at 10 mg/kg p.o. Moreover, the eosinophil-adherence to HUVEC was inhibited by VUF-K-8788 at the concentration of 10-30 microM. In conclusion, this inhibitory effect of VUF-K-8788 on eosinophil-adherence might contribute to the prevention of LAR and infiltration by eosinophils in the experimental asthmatic model in guinea pigs.

Pharmacological characterization of the new histamine H4 receptor agonist VUF 8430.[Pubmed:19413569]

Br J Pharmacol. 2009 May;157(1):34-43.

BACKGROUND AND PURPOSE: We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine. EXPERIMENTAL APPROACH: Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity. KEY RESULTS: Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. CONCLUSIONS AND IMPLICATIONS: Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors.

VUF10166, a novel compound with differing activities at 5-HT(3)A and 5-HT(3)AB receptors.[Pubmed:22306960]

J Pharmacol Exp Ther. 2012 May;341(2):350-9.

The actions of a novel, potent 5-HT(3) receptor ligand, [2-chloro-(4-methylpiperazine-1-yl)quinoxaline (VUF10166)], were examined at heterologously expressed human 5-HT(3)A and 5-HT(3)AB receptors. VUF10166 displaced [(3)H]granisetron binding to 5-HT(3)A receptors expressed in human embryonic kidney cells with high affinity (K(i) = 0.04 nM) but was less potent at 5-HT(3)AB receptors (K(i) = 22 nM). Dissociation of [(3)H]granisetron in the presence of VUF10166 was best fit with a single time constant (t(1/2) = 53 min) at 5-HT(3)A receptors, but with two time constants (t(1/2) = 55 and 2.4 min) at 5-HT(3)AB receptors. Electrophysiological studies in oocytes revealed that VUF10166 inhibited 5-HT-induced responses at 5-HT(3)A receptors at nanomolar concentrations, but inhibition and recovery were too slow to determine an IC(5)(0). At 5-HT(3)AB receptors, inhibition and recovery were faster, yielding an IC(5)(0) of 40 nM. Cysteine substitutions in the complementary (-), but not the principal (+), face of the 5-HT(3)B subunit produced heteromeric receptors in which the actions of VUF10166 resembled those at homomeric receptors. At 5-HT(3)A receptors, VUF10166 at higher concentrations also behaved as a partial agonist (EC(5)(0) = 5.2 muM; R(max) = 0.24) but did not elicit significant responses at 5-HT(3)AB receptors at

Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo.[Pubmed:18357976]

J Med Chem. 2008 Apr 24;51(8):2457-67.

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 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R 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(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.

VUF10166 is a novel, potent and competitive antagonist for 5-HT3A receptor with Ki of 0.04 nM, its affinity at 5-HT3AB receptor is significantly lower.

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