Desloratadine inhibits constitutive and histamine-stimulated nuclear factor-kappaB activity consistent with inverse agonism at the histamine H1 Receptor.
BACKGROUND
The human histamine H1 receptor is constitutively active and exhibits basal activation of nuclear factor-kappaB (NF-kappaB), an important modulator of allergic inflammation. Certain H1 antihistamines have recently been shown to inhibit basal NF-kappaB 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-kappaB activity and compared it with the activities of other H1 antihistamines.


RESULTS
Transiently transfected COS-7 cells co-expressing NF-kappaB-luciferase and the H1 receptor exhibited constitutive NF-kappaB activity. H1 antihistamines reduced basal NF-kappaB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-kappaB 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-kappaB activity in the absence of the H1 receptor.


CONCLUSIONS
Desloratadine, acting through the histamine H1 receptor, inhibited basal NF-kappaB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-kappaB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.
Wu
Ren-Long
RL
Schering-Plough Research Institute, Schering-Plough Corporation, Kenilworth, NJ 07033, USA.
Anthes
John C
JC
Kreutner
William
W
Harris
Alan G
AG
West
Robert E
RE
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006632:Histamine / Q000276:immunology / Q000494:pharmacology*; D017442:Histamine Agonists / Q000276:immunology / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D017336:Loratadine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology; D011969:Receptors, Histamine H1 / Q000276:immunology*
D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D016328:NF-kappa B; D011969:Receptors, Histamine H1; D017336:Loratadine; D006632:Histamine; C121345:desloratadine