Effect of combined histamine H1 and H3 receptor blockade on cutaneous microvascular permeability elicited by compound 48/80.

The pharmacological consequences of combining a histamine H1 receptor antagonist with a H3 antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H1 antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 +/- 4, 31 +/- 4, 32 +/- 4 and 37 +/- 4%, respectively. Combination treatment with an H1 and H3 antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H3 antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 +/- 4, 45 +/- 4, 49 +/- 4 and 54 +/- 4%. A second H3 antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H1 and a H3 histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H1 or H3 antagonist administered separately. In addition, the antiallergy activity of combining a H3 antihistamine with a H3 antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.

Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor.

We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.

SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist.

Experiments were performed to characterize the pharmacology of SCH 206272 [(R,R)-1'[5-[(3,5-dichlorobenzoyl)methylamino]-3-(3,4-dichlorophenyl)-4(Z)-(methoxyimino)pentyl]-N-methyl-2-oxo-[1,4'bipiperidine]-3-acetamide] as a potent and selective antagonist of tachykinin (NK) NK(1), NK(2), and NK(3) receptors. SCH 206272 inhibited binding at human tachykinin NK(1), NK(2), and NK(3) receptors (K(i) = 1.3, 0.4, and 0.3 nM, respectively) and antagonized [Ca(2+)](i) mobilization in Chinese hamster ovary (CHO) cells expressing the cloned human tachykinin NK(1), NK(2), or NK(3) receptors. SCH 206272 inhibited relaxation of the human pulmonary artery (pK(b) = 7.7 +/- 0.3) induced by the tachykinin NK(1) receptor agonist, [Met-O-Me] substance P and contraction of the human bronchus (pK(b = 8.2 +/- 0.3) induced by the tachykinin NK(2) receptor agonist, neurokinin A. In isolated guinea pig tissues, SCH 206272 inhibited substance P-induced enhancement of electrical field stimulated contractions of the vas deferens, (pK(b = 7.6 +/- 0.2), NKA-induced contraction of the bronchus (pK(b) = 7.7 +/- 0.2), and senktide-induced contraction of the ileum. In vivo, oral SCH 206272 (0.1-10 mg/kg, p.o.) inhibited substance P-induced airway microvascular leakage and neurokinin A-induced bronchospasm in the guinea pig. In a canine in vivo model, SCH 206272 (0.1-3 mg/kg, p.o.) inhibited NK(1) and NK(2) activities induced by exogenous substance P and neurokinin A. Furthermore, in guinea pig models involving endogenously released tachykinins, SCH 206272 inhibited hyperventilation-induced bronchospasm, capsaicin-induced cough, and airway microvascular leakage induced by nebulized hypertonic saline. These data demonstrate that SCH 206272 is a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. This compound may have beneficial effects in diseases thought to be mediated by tachykinins, such as cough, asthma, and chronic obstructive pulmonary disease.

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.

Pharmacology of N-(3,5-dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591), a novel, orally active phosphodiesterase 4 inhibitor.

N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC(50) = 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC(50) = 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suum-induced lung eosinophilia was blocked. Hyperventilation-induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10- to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD.