Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.
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 wit...
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2012-01-01
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doaj-90307ebb3d9b4635b7699d94b8b1d2bb2020-11-25T01:00:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4218510.1371/journal.pone.0042185Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor.Ying ShiRong ShengTingting ZhongYu XuXiaopan ChenDong YangYi SunFenyan YangYongzhou HuNaiming ZhouThe 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.http://europepmc.org/articles/PMC3411647?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ying Shi Rong Sheng Tingting Zhong Yu Xu Xiaopan Chen Dong Yang Yi Sun Fenyan Yang Yongzhou Hu Naiming Zhou |
spellingShingle |
Ying Shi Rong Sheng Tingting Zhong Yu Xu Xiaopan Chen Dong Yang Yi Sun Fenyan Yang Yongzhou Hu Naiming Zhou Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. PLoS ONE |
author_facet |
Ying Shi Rong Sheng Tingting Zhong Yu Xu Xiaopan Chen Dong Yang Yi Sun Fenyan Yang Yongzhou Hu Naiming Zhou |
author_sort |
Ying Shi |
title |
Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. |
title_short |
Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. |
title_full |
Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. |
title_fullStr |
Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. |
title_full_unstemmed |
Identification and characterization of ZEL-H16 as a novel agonist of the histamine H3 receptor. |
title_sort |
identification and characterization of zel-h16 as a novel agonist of the histamine h3 receptor. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3411647?pdf=render |
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