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In vitro and in vivo characterization of A‐940894: a potent histamine H 4 receptor antagonist with anti‐inflammatory properties
Author(s) -
Strakhova MI,
Cuff CA,
Manelli AM,
Carr TL,
Witte DG,
Baranowski JL,
Vortherms TA,
Miller TR,
Rundell L,
McPherson MJ,
Adair RM,
Brito AA,
Bettencourt BM,
Yao BB,
Wetter JM,
Marsh KC,
Liu H,
Cowart MD,
Brioni JD,
Esbenshade TA
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00236.x
Subject(s) - histamine , histamine h4 receptor , pharmacology , histamine receptor , in vivo , zymosan , histamine h2 receptor , mast cell , receptor , chemistry , receptor antagonist , biology , antagonist , in vitro , immunology , biochemistry , microbiology and biotechnology
Background and purpose: The histamine H 4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti‐inflammatory properties of a potent histamine H 4 receptor antagonist, A‐940894 (4‐piperazin‐1‐yl‐6,7‐dihydro‐5H‐benzo[6,7]cyclohepta[1,2‐d]pyrimidin‐2‐ylamine). Experimental approach: We have analysed the pharmacological profile of A‐940894 at mouse native, rat recombinant and human recombinant and native, histamine H 4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan‐induced peritonitis. Key results: A‐940894 potently binds to both human and rat histamine H 4 receptors and exhibits considerably lower affinity for the human histamine H 1 , H 2 or H 3 receptors. It potently blocked histamine‐evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine‐induced shape change of mouse bone marrow‐derived mast cells and chemotaxis of human eosinophils in vitro . In a mouse mast cell‐dependent model of zymosan‐induced peritonitis, A‐940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D 2 levels. Finally, A‐940894 has good pharmacokinetic properties, including half‐life and oral bioavailability in rats and mice. Conclusions and Implications: These data suggest that A‐940894 is a potent and selective histamine H 4 receptor antagonist with pharmacokinetic properties suitable for long‐term in vivo testing and could serve as a useful tool for the further characterization of histamine H 4 receptor pharmacology.