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CELLULAR AND MOLECULAR

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

Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (H.D.L., R.M.v.R., R.A.B., R.L.); and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, California (P.L., R.L.T.)

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 (K_i = 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; = 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.

Address correspondence to: Dr. R. Leurs, Leiden/Amsterdam Center for Drug Research, Department of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. E-mail: r.leurs{at}few.vu.nl

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