RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1310
OP 1321
DO 10.1124/jpet.105.087965
VO 314
IS 3
A1 Herman D. Lim
A1 Richard M. van Rijn
A1 Ping Ling
A1 Remko A. Bakker
A1 Robin L. Thurmond
A1 Rob Leurs
YR 2005
UL http://jpet.aspetjournals.org/content/314/3/1310.abstract
AB The histamine H4 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 (hH4R) 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 [3H]histamine binding to the hH4R at concentrations up to 10 μM. Most of the tested H2R agonists and imidazole-based H3R ligands show micromolar-to-nanomolar range hH4R affinity, and these ligands exert different intrinsic hH4R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H4R ligand (Ki = 50 nM) that has a >100-fold selectivity for the hH4R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH4R (pEC50 = 7.4 ± 0.1; α = 1), and this response was competitively antagonized by the selective H4R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA2 = 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. The American Society for Pharmacology and Experimental Therapeutics