Paradoxical stimulatory effects of the “standard” histamine H4-receptor antagonist JNJ7777120: The H4-receptor joins the club of 7TM receptors exhibiting functional selectivity

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 the afore-mentioned 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 (Rosethorne and Charlton, Mol Pharmacol (2011), in press; Schnell et al., Naunyn-Schmiedeberg's Arch Pharmacol (2011), in press) 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 signalling, 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 dilemma that, currently, there is no "standard" H4R antagonist available to the scientific community.