H4 receptor inverse agonists(Griffin)

Glycogen synthase kinase 3β (GSK-3β) is a potential target for anti-Alzheimer's disease (AD) drug development. In this study, a series of novel thieno[3,2-c]pyrazol-3-amine derivatives was synthesized and evaluated as potential GSK-3β inhibitors by structure-based drug design. The thieno[3,2-c]pyrazol-3-amine derivative 54 with a 4-methylpyrazole moiety which interacted with Arg141 by π-cation interaction was identified as a potent GSK-3β inhibitor with an IC₅₀ of 3.4 nM and an acceptable kinase selectivity profile. In the rat primary cortical neurons, compound 54 showed neuroprotective effects on Aβ-induced neurotoxicity. Western blot analysis indicated that 54 inhibited GSK-3β by up-regulating the expression of phosphorylated GSK-3β at Ser9 and down-regulating the expression of phosphorylated GSK-3β at Tyr216. Meanwhile, 54 decreased tau phosphorylation at Ser396 in a dose-dependent way. In astrocytes and microglia cells, 54 inhibited the expression of inducible nitric oxide synthase (iNOS), indicating that 54 showed an anti-neuroinflammatory effect. In the AlCl₃-induced zebrafish AD model, 54 significantly ameliorated the AlCl₃-induced dyskinesia, demonstrating its anti-AD activity in vivo.

After the recent description of β-arrestin2 recruitment to the human histamine H₄ receptor (hH₄R) in response to the well known H₄R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH₄R ligands to induce Gα(i) protein signaling and β-arrestin2 recruitment by the hH₄R. The selected hH(4)R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH₄R ligands with a significant bias for the Gα(i) protein or β-arrestin2 pathway on the basis of efficacy differences. In addition, hH₄R antagonists that did not show positive efficacy in either functional readouts were found. A common trend in pathway preference for the nine different ligand classes could not be observed. In particular, the isothiourea class shows very diverse results, varying from Gα(i) protein-biased or β-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH₄R ligands are important pharmacological tools to unravel the significance of biased hH₄R signaling in H₄R pharmacology.