Seifert, Roland and Schneider, Erich H. and Dove, Stefan and Brunskole, Irena and Neumann, Detlef and Strasser, Andrea and Buschauer, Armin (2011) Paradoxical Stimulatory Effects of the "Standard" Histamine H-4-Receptor Antagonist JNJ7777120: the H-4 Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity. MOLECULAR PHARMACOLOGY, 79 (4). pp. 631-638. ISSN 0026-895X, 1521-0111
Full text not available from this repository. (Request a copy)Abstract
The histamine H-4 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 beta-arrestin in a supposedly G(i)-protein-independent (pertussis toxin-insensitive) manner and that at certain H4R species orthologs, JNJ7777120 exhibits partial agonist efficacy with respect to G(i)-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-COUPLED RECEPTOR; 1ST POTENT; PHARMACOLOGY; INFLAMMATION; ACTIVATION; KINASES; BINDING; MOUSE; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) Chemistry and Pharmacy > Institute of Pharmacy > Pharmacology and Toxicology (Prof. Schlossmann, formerly Prof. Seifert) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Jun 2020 08:37 |
| Last Modified: | 23 Jun 2020 08:37 |
| URI: | https://pred.uni-regensburg.de/id/eprint/21081 |
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