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 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.