title: C-027 inhibits IgE-mediated passive sensitization bronchoconstriction and acts as a histamine and serotonin antagonist in human airways.
abstract: Atopic asthma is poorly controlled by current therapies. Newer therapies and novel antihistamines are, therefore, required to treat patients whose atopic asthma is not controlled. For the first time, C-027 is shown to antagonize histamine, IgE-mediated and serotonin-induced contraction in human airways and vessels. Human precision-cut lung slices (PCLS, 250 μm thick), containing an airway or blood vessel, were pretreated with either C-027 (2 hours) or with vehicle alone and were contracted with histamine or serotonin. Known antihistamine was used as a comparator in antihistamine studies. Also, human airways were contracted via IgE passive sensitization in the presence or absence of C-027 or fexofenadine. Affinity of C-027 toward human G-protein coupled receptors was also determined, as well as the drug's biodistribution in murine model. C-027 was shown to have the highest affinity toward human histamine and serotonin receptors. Subsequently, C-027 was shown to antagonize histamine- and serotonin-induced airway and vascular smooth muscle contraction, respectively, and histamine-released bronchocontraction mediated by IgE passive sensitization in human small airways. C-027 also inhibited histamine-mediated single-cell calcium ion release. Low levels of C-027 were found in murine brain tissue. Collectively, these data suggest that C-027 markedly inhibits IgE-induced bronchoconstriction and antagonizes histamine and serotonin-contraction with little biodistribution in the brain. The compound may offer a future therapy for allergen-induced airway hyperresponsiveness in patients with asthma.
authors.affiliation: Department of Medicine and the Airway Biology Initiative, University of Pennsylvania, Philadelphia, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Cooper
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Gautam
authors.initials: G
authors.lastname: Damera
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.forename: David A
authors.initials: DA
authors.lastname: Zopf
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D016535:Bronchial Hyperreactivity / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology*; D051379:Mice; D010640:Phenothiazines / Q000378:metabolism / Q000494:pharmacology*; D010879:Piperazines; D011968:Receptors, Histamine / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C569749:2-amino-N-(2-(4-(3-(2-trifluoromethylphenothiazin-10-yl)propyl)piperazin-1-yl)ethyl)acetamide; D000081:Acetamides; D006633:Histamine Antagonists; D010640:Phenothiazines; D010879:Piperazines; D011968:Receptors, Histamine; D012702:Serotonin Antagonists; D007073:Immunoglobulin E; D006632:Histamine; D002118:Calcium