Tachykinin receptors in chronic inflammatory lower airway diseases

Abstract

Preclinical models have highlighted the blockade of tachykinin NK1, NK2 and NK3 receptors as ideal targets for inflammatory lower airway diseases such as asthma and chronic obstructive pulmonary disease. In fact, NK1 antagonists reduce pulmonary neurogenic and non-neurogenic inflammation in several allergic and non-allergic models. Likewise, NK2 receptor antagonists have the potential to reduce airway motor responses by a local action on smooth muscle tone, by preventing airway hyperreactivity, and airway reflexes. NK3 antagonists join some properties of NK1 and NK2 receptor blockers as they are able to reduce both inflammatory and motor components in models of airway dysfunctions. Despite this evidence, early phase clinical testing of selective or mixed tachykinin antagonists have been largely disappointing. In fact, at doses selected for antagonising neurokinin A-induced bronchoconstriction, these compounds were inactive on bronchoconstriction induced by other kinds of challenge and did not reduce asthmatic symptoms or airway hyperreactivity following a brief course of treatment. The hope that these compounds could serve as disease controllers following a long-term treatment still remains, but the difficulties in the clinical testing of this hypothesis have discouraged most of the companies that have stopped development of tachykinin antagonists for these indications.