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

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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.

Author: Ying Shi, Rong Sheng, Tingting Zhong, Yu Xu, Xiaopan Chen, Dong Yang, Yi Sun, Fenyan Yang, Yongzhou Hu , Naiming Zhou



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