Analysis of Multiple Histamine H₄ Receptor Compound Classes Uncovers Gα_i Protein- and β-Arrestin2-Biased Ligands

Abstract

After the recent description of ␤-arrestin2 recruitment to the human histamine H 4 receptor (hH 4 R) in response to the well known H 4 R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH 4 R ligands to induce G␣ i protein signaling and ␤-arrestin2 recruitment by the hH 4 R. The selected hH 4 R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH 4 R ligands with a significant bias for the G␣ i protein or ␤-arrestin2 pathway on the basis of efficacy differences. In addition, hH 4 R antagonists that did not show positive efficacy in either functional readouts were found. A common trend in pathway preference for the nine different ligand classes could not be observed. In particular, the isothiourea class shows very diverse results, varying from G␣ i protein-biased or ␤-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH 4 R ligands are important pharmacological tools to unravel the significance of biased hH 4 R signaling in H 4 R pharmacology.

The Effective Application of Biased Signaling to New Drug Discovery

“…Very different EC 50 values for partial agonists also have been reported for m-opioid receptors (McPherson et al, 2010;Nickolls et al, 2011), histamine H 4 receptors (Nijmeijer et al, 2012), and b 1 -adrenoceptors (Casella et al, 2011). This suggests that effective bias may be obtained through combinations of efficacies and affinities for the receptor as it interacts with different pathways.…”

Differential Impact of Amino Acid Substitutions on Critical Residues of the Human Glucagon-Like Peptide-1 Receptor Involved in Peptide Activity and Small-Molecule Allostery

“…Of note, differences in functional K A values derived from fitting the operational model may arise from the presence of noninterconverting states that are unique to ligand-receptor-effector complexes (Leff et al, 1997;Holst et al, 2001;Zheng et al, 2008;McPherson et al, 2010;Strachan et al, 2010;Nijmeijer et al, 2012), and this is observed for peptide agonists at the wild-type GLP-1R (Supplemental Table S2). …”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…The reported biased H 4 receptor signaling by JNJ-7777120 has in the meantime been extended to a broader range of benzimidazole analogs (Nijmeijer et al, 2013), but testing a variety of known H 4 receptor ligands has resulted in the identification of biased ligands for both the G protein and b-arrestin pathways (Nijmeijer et al, 2012).…”