Inhibition of Guinea Pig Complement by Maleopimaric Acid and Other Derivatives of Levopimaric Acid

Abstract

Summary Diels Alder addition products of levopimaric acid are a class of newly discovered potent inhibitors of guinea pig complement. Maleopimaric acid, one of the most potent inhibitors in this class, was chosen to study the sites in the complement sequence where the inhibition occurred. Maleopimaric acid inhibits the formation of EAC′1a from C′ and EA and promotes the dissociation of C′1a from EAC′1a. This latter action does not appear to occur through a chelation of Ca ++. The inhibitor does not affect the stability of binding of C′4 to EAC′4. The formation of EAC′1a,4,2a from EAC′1a,4 + C′2 is depressed by maleopimaric acid. This inhibition is greater than can be accounted for by the action of maleopimaric acid on C′1a. Maleopimaric acid does not change the rate of decay of C′2a on EAC′1a,4,2a, nor does it act by chelating Mg ++. The formation of EAC′1a,4,2a,3 from C′3 + EAC′1a,4,2a is not interfered with nor is the immune adherence activity of the former intermediate affected by maleopimaric acid. In the presence of the inhibitor EAC′1a,4,2a,3,5, EAC′1a,4,2a,3,5,6 and EAC′1a,4,2a,3,5,6,7 cannot be generated with purified components from the appropriate preceding intermediates. Maleopimaric acid prevents the generation in rabbit serum of chemotactic activity from the activated (C′5, C′6, C′7)ac complex, and inhibits the activity of the already formed chemotactic factor by dissociating it. Not inhibited by maleopimaric acid are the addition of C′8 and C′9 activity to EAC′1a,4,3,5,6,7 and the subsequent conversion to E*.