Abstract
The histamine H4 receptor (H4R) is expressed in several cell types of the immune system and is assumed to play an important pro-inflammatory role in various diseases, including bronchial asthma, atopic dermatitis, and pruritus. Accordingly, H4R antagonists have been suggested to provide valuable drugs for the treatment of these diseases. Over the past decade, the indole derivative 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120) has become the “standard” H4R antagonist and has been extensively used to assess the pathophysiological role of the H4R. However, the situation has now become more complicated by recent data (p. 749 and Naunyn Schmiedebergs Arch Pharmacol doi: 10.1007/s00210-011-0612-3) showing that JNJ7777120 can also activate β-arrestin in a supposedly Gi-protein-independent (pertussis toxin-insensitive) manner and that at certain H4R species orthologs, JNJ7777120 exhibits partial agonist efficacy with respect to Gi-protein activation (steady-state high-affinity GTPase activity). These novel findings can be explained within the concept of functional selectivity or biased signaling, assuming unique ligand-specific receptor conformations with distinct signal transduction capabilities. Thus, great caution must be exerted when interpreting in vivo effects of JNJ7777120 as H4R antagonism. We discuss future directions to get out of the current dilemma in which there is no “standard” H4R antagonist available to the scientific community.
Footnotes
This work was supported by the Deutsche Forschungsgemeinschaft [Grants GRK 760, GRK 1441, SFB 587, STR 1125/1-1] and the European Union [COST program BM0806 (H4R network)].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/mol.111.071266.
Please see the related article on page 749.
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ABBREVIATIONS:
- GTPγS
- guanosine 5′-O-(3-thio)triphosphate
- JNJ7777120
- 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine
- 7TM
- seven-transmembrane domain
- HxR
- histamine H1- H2-, H3 or H4 receptor
- c
- canine
- h
- human
- m
- mouse
- r
- rat
- PTX
- pertussis toxin
- ERK
- extracellular signal-regulated kinase
- UR-PI376
- 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine
- UR-PI294
- N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine.
- Received January 16, 2011.
- Accepted January 25, 2011.
- Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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