Correction: Identification and Characterization of ZEL-H16 as a Novel Agonist of the Histamine H₃Receptor

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.

Synthesis and antiseizure effect evaluation of nonimidazole histamine H3receptor antagonists containing the oxazole moiety

“…The CRE reporter gene assay has been used extensively to evaluate the efficacy of GPCR antagonists or agonists. [ 35,36 ] In this study, the H 3 R antagonistic activities of the prepared 3‐(4‐(2‐methyloxazol‐4‐yl)phenoxy)propylamine derivatives were screened by the CRE‐driven luciferase assay, in which the HEK‐293 cells expressed the human H 3 R and a reporter gene consisting of the firefly luciferase coding region was used. Thioperamide, an H 3 R antagonist, and PIT, an antagonist/inverse agonist of H 3 R with in vivo antiepileptic activity, were chosen as the positive control.…”

“…The crystal structure of the histamine H 1 receptor (PDB ID: 3RZE) was used to construct the H 3 receptor homology model. [ 36 ] The hH 3 R primary sequence was downloaded from the Universal Protein Resource (UniProt ID: Q9Y5N1). DS MODELER (Discovery Studio 2019) was used to construct a 3D model of the H 3 R. Then the model was assessed in accordance with the PDF total energy and the 3D profile procedure.…”