title: Profiling of histamine H4 receptor agonists in native human monocytes.
abstract: OBJECTIVE
  Since the identification of the histamine H₄ receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G-protein signalling components. In this study we investigated the specific properties of H₄ receptor ligands in native cells.
  
  
  METHODS
  Histamine and five different H₄ receptor agonists - 4-methylhistamine, UR-PI376, clobenpropit, VUF8430 and ST-1006 - were characterized in freshly isolated human monocytes. The ligands (10 nM-10 μM) were tested as inhibitors of IL-12p70 secretion from human monocytes and the effects of the H₂ receptor antagonist ranitidine and the H₄ receptor antagonist JNJ7777120 on their action was investigated.
  
  
  RESULTS
  Histamine and all the tested agonists reduced IL-12p70 secretion into monocyte supernatants by 40-70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H₂ or H₄ receptor antagonists showed that some H₄ receptor ligands also had low activity at the H₂ receptor.
  
  
  CONCLUSIONS
  Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H₄ receptor ligands in native cells.
authors: Department of Dermatology and Allergy, Hannover Medical School, Germany. maria.gschwandtner@meduniwien.ac.at
authors: M
authors: M
authors: Gschwandtner
authors: B
authors: B
authors: Koether
authors: T
authors: T
authors: Werfel
authors: H
authors: H
authors: Stark
authors: R
authors: R
authors: Gutzmer
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism*; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018664:Interleukin-12 / Q000378:metabolism; D008024:Ligands; D009000:Monocytes / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism; D000074040:Receptors, Histamine H4; D014162:Transfection
chemical_list: C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007211:Indoles; D008024:Ligands; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D000074040:Receptors, Histamine H4; D018664:Interleukin-12; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D006632:Histamine; D011899:Ranitidine
keywords: 4-methylhistamine; ST-1006; UR-PI376; VUF8430; clobenpropit; histamine; histamine H4 receptor
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