Publikationsdatenbank

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice (2023)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Uluckan, Özge

Bruno, Sandro

Wang, Yichen

Wack, Nathalie

Wilzopolski, Jenny (WE 14)

Goetschy, Jean-Francois

Delucis-Bronn, Corinne

Urban, Beatrice

Fehlmann, Dominique

Stark, Holger

Hauchard, Alice

Roussel, Elsa

Kempf, Dominique

Kaupmann, Klemens

Raulf, Friedrich

Bäumer, Wolfgang (WE 14)

Röhn, Till A.

Zerwes, Hans Günter

Quelle

European journal of pharmacology

Bandzählung: 945

Seiten: Artikel 175533

ISSN: 1879-0712

Sprache

Englisch

Verweise

URL (Volltext): https://www.sciencedirect.com/science/article/abs/pii/S0014299923000444

DOI: 10.1016/j.ejphar.2023.175533

Pubmed: 36690055

Kontakt

Institut für Pharmakologie und Toxikologie

Koserstr. 20
14195 Berlin
+49 30 838 53221
pharmakologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Background:
Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells.

Objective:
During the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca2+ flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated.

Results:
We show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca2+ flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model.

Conclusions:
Our results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.