title: Analysis of multiple histamine H₄ receptor compound classes uncovers Gαi protein- and β-arrestin2-biased ligands.
abstract: After the recent description of β-arrestin2 recruitment to the human histamine H₄ receptor (hH₄R) in response to the well known H₄R antagonist 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methyl-piperazine (JNJ 7777120), we evaluated in this study the efficacy of 31 known hH₄R ligands to induce Gα(i) protein signaling and β-arrestin2 recruitment by the hH₄R. The selected hH(4)R ligands belong to nine different structural classes that partly cover (pre)clinical trial candidates. We have identified hH₄R ligands with a significant bias for the Gα(i) protein or β-arrestin2 pathway on the basis of efficacy differences. In addition, hH₄R 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 Gα(i) protein-biased or β-arrestin2-biased to nonbiased antagonists upon minor structural changes. The identified biased hH₄R ligands are important pharmacological tools to unravel the significance of biased hH₄R signaling in H₄R pharmacology.
authors.affiliation: VU University Amsterdam, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Rosethorne
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Charlton
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D019390:Arrestins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D010879:Piperazines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C418607:HRH4 protein, human; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D000071557:beta-Arrestins; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go