Abstract
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 Gαi protein signaling and β-arrestin2 recruitment by the hH4R. The selected hH4R 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 Gαi 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 Gαi 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.
Footnotes
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
S.N., H.F.V., and R.L. participate in the European COST BM0806.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- H4R
- histamine H4 receptor
- hH4R
- human histamine H4 receptor
- GPCR
- G protein-coupled receptor
- ERK
- extracellular signal-regulated kinase
- PTx
- pertussis toxin
- EFC
- enzyme fragment complementation
- JNJ 7777120
- 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine
- HEK293T
- human embryonic kidney cells expressing the large T-antigen of simian virus 40
- CRE
- cAMP response element
- 4-MeHA
- 4-methylhistamine.
- Received June 29, 2012.
- Accepted September 12, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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