PT - JOURNAL ARTICLE AU - Roland Seifert AU - Erich H. Schneider AU - Stefan Dove AU - Irena Brunskole AU - Detlef Neumann AU - Andrea Strasser AU - Armin Buschauer TI - Paradoxical Stimulatory Effects of the “Standard” Histamine H<sub>4</sub>-Receptor Antagonist JNJ7777120: the H<sub>4</sub> Receptor Joins the Club of 7 Transmembrane Domain Receptors Exhibiting Functional Selectivity AID - 10.1124/mol.111.071266 DP - 2011 Apr 01 TA - Molecular Pharmacology PG - 631--638 VI - 79 IP - 4 4099 - http://molpharm.aspetjournals.org/content/79/4/631.short 4100 - http://molpharm.aspetjournals.org/content/79/4/631.full SO - Mol Pharmacol2011 Apr 01; 79 AB - 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.