Identification and Characterization of ZEL-H16 as a Novel Agonist of the Histamine H3 Receptor

Abstract

The histamine H3 receptor (H3R) has been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. In this study, a non-imidazole compound, ZEL-H16, was identified as a novel histamine H3 receptor agonist. ZEL-H16 was found to bind to human H3R with a Ki value of approximately 2.07 nM and 4.36 nM to rat H3R. Further characterization indicated that ZEL-H16 behaved as a partial agonist on the inhibition of forskolin-stimulated cAMP accumulation (the efficacy was 60% of that of histamine) and activation of ERK1/2 signaling (the efficacy was 50% of that of histamine) at H3 receptors, but acted as a full agonist just like histamin in the guinea-pig ileum contraction assay. These effects were blocked by pertussis toxin and H3 receptor specific antagonist thioperamide. ZEL-H16 showed no agonist or antagonist activities at the cloned human histamine H1, H2, and H4 receptors and other biogenic amine GPCRs in the CRE-driven reporter assay. Furthermore, our present data demonstrated that treatment of ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is a novel and potent nonimidazole agonist of H3R, which might serve as a pharmacological tool for future investigations or as possible therapeutic agent of H3R.

Visualization of the activation of the histamine H3 receptor (H3R) using novel fluorescence resonance energy transfer biosensors and their potential application to the study of H3R pharmacology

“…1F,G). This is consistent with the H3R FRET sensor internalizing upon agonist treatment in a similar way to the wild-type H3R [43].…”

The expression and function of histamine H3 receptors in pancreatic beta cells

“…H 3 receptors could be expressed not only in beta cells but also in these other cell types. H 3 receptor protein was detected in the cytoplasm in addition to the plasma membrane (Figure C,D), suggesting that some of the H 3 receptors are internalized by ligand binding in pancreatic beta cells (Shi et al ., ).…”

Agonist‐induced activation of histamine H3 receptor signals to extracellular signal‐regulated kinases 1 and 2 through PKC‐, PLD‐, and EGFR‐dependent mechanisms

“…Our previous data, using a HEK293 cell line stably expressing human H3R, has shown that H3R triggers ERK1/2 phosphorylation in a concentration and time‐dependent manner in response to an agonist (Shi et al . ). Here, we used the same stable HEK293‐H3R cell line and cultured mouse cortical neurons, which endogenously express H3R, to characterize the signaling pathway of H3R‐mediated ERK1/2 activation.…”

“…Our own previous study had demonstrated that the partial agonist ZEL‐H16 could activate ERK1/2 signaling pathway and that this effect was almost completely blocked by co‐incubation with thioperamide and PTX (Shi et al . ). In this study, we clearly demonstrate that stimulation of histamine or imetit triggers ERK1/2 phosphorylation in both HEK293 cells and cultured cortical neurons.…”