Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor:: Identification of 4-methylhistamine as the first potent and selective H4 receptor agonist

The histamine H-4 receptor (H4R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H4R agonists have not been identified. In the present study, we therefore evaluated the human H4R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H1R and H2R antagonists, including several important therapeutics, displaced less than 30% of specific [H-3]histamine binding to the hH(4)R at concentrations up to 10 mu M. Most of the tested H2R agonists and imidazole-based H3R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H4R ligand (K-i = 50 nM) that has a > 100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H 4 R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent H4R agonist is of major importance for future studies to unravel the physiological roles of the H4R.