Background: The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-ĸB (NF-ĸB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-ĸB activity by stabilizing the H1 receptor in an inactive state, a phenomenon called ‘inverse agonism’. Methods: We evaluated the effect of the new H1 antihistamine, desloratadine, on basal and histamine-stimulated NF-ĸB activity and compared it with the activities of other H1 antihistamines. Results: Transiently transfected COS-7 cells co-expressing NF-ĸB-luciferase and the H1 receptor exhibited constitutive NF-ĸB activity. H1 antihistamines reduced basal NF-ĸB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-ĸB activity 8-fold, which was blocked by H1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-ĸB activity in the absence of the H1 receptor. Conclusions: Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-ĸB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-ĸB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.

Keywords:
Desloratadine, Inverse agonism, NF-kappaB, Antihistamine, Human histamine H1 receptor
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2004
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