Abstract
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.
Footnotes
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R.L. is a recipient of a PIONIER award of the Technology Foundation (Stichting voor de Technische Wetenschapppen) of the Netherlands Foundation of Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.087965.
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ABBREVIATIONS: HxR, histamine Hx receptor; hH4R, human histamine H4 receptor; IL, interleukin; JNJ 7777120, 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine; VUF 6002, 1-[(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine; VUF 4742, N-(4-chlorobenzyl)-N′-[5-(4(5)-imidazolyl)pentyl]thiourea; OUP-16, 2-cyano-1-methyl-1–3-{(2R,5R)-5-[1H-imidazol-4(5)-yl]tetrahydrofuran-2-yl}methylguanidine; PEA, 2-pyridylethylamine; TEA, 2-(2-thiazolyl)ethylamine; VUF 8328, S-[3-(4(5)-imidazolyl)propyl]isothiourea; ORG3770, 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2]benzazepine; CRE, cAMP response element; BMMC, bone marrow mast cell; JNJ 637940, 7-methyl-2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine; A-349821, 4′-{3-[(R,R)2,5-dimethyl-pyrrolidin-1-yl]-propoxy)-biphenyl-4-yl}-morpholin-4-yl-methanone; VUF 4683, 1-[4-(imidazol-4-yl)-butyl)-3-isopropyl-thiourea; VUF 4616, 1-[5-(imidazol-4-yl)-pentyl]-3-isopropyl-thiourea; VUF 4617, 1-cyclohexyl-3-[5-(imidazol-4-yl)-pentyl]-thiourea.
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↵1 These authors contributed equally.
- Received April 13, 2005.
- Accepted June 1, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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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
