Selective Inhibitor of Slow Reacting Substance of Anaphylaxis

Abstract

IN the guinea-pig, anaphylaxis in the lung leads to the release of slow reacting substance of anaphylaxis (SRS-A) and histamine. Because the bronchoconstriction which accompanies anaphylaxis is greatly reduced by antihistamine drugs, histamine is thought to be the more important physiological mediator. But anaphylaxis induced in the human lung by antigen challenge and measured by alterations in the forced expiratory volume is only marginally reduced by antihistamine drugs¹. Studies in vitro on lung tissue from asthmatic patients have shown that histamine and SRS-A are released in the anaphylactic reaction² and this has been confirmed on passively sensitized human lung from non-asthmatic patients³. There is some evidence⁴ to suggest that SRS-A may be physiologically more important as a mediator of anaphylaxis in man. Compounds produced in our laboratories have therefore been screened as antagonists of contractions of isolated guinea-pig ileum induced by SRS-A. From the structure activity relationships which have emerged, we developed a number of potent and specific antagonists of which FPL 55712 (Fig. 1) is an example. Here we describe the activity of the racemic mixture of the sodium salt of this compound as an antagonist of unpurified guinea-pig and human SRS-A and partially purified rat SRS-A.