C-027 inhibits IgE-mediated passive sensitization bronchoconstriction and acts as a histamine and serotonin antagonist in human airways

Philip R. Cooper, Jie Zhang, Gautam Damera, Toshinori Hoshi, David A. Zopf, Reynold A. Panettieri

Research output: Contribution to journalArticle

13 Scopus citations

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 histaminereleased bronchocontraction mediated by IgE passive sensitization in human small airways. C-027 also inhibited histaminemediated 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.

Original languageEnglish (US)
Pages (from-to)359-365
Number of pages7
JournalAllergy and Asthma Proceedings
Volume32
Issue number5
DOIs
StatePublished - Sep 1 2011

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Pulmonary and Respiratory Medicine

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