Comparative potency and pharmacology of isomers of leukotriene D4 on guinea-pig trachea: requirement for a 5(S)6(R) configuration

Abstract

The relative contractile activity of C5 and C6 diastereomers of Leukotriene D4 (LTD4), as well as 11-trans stereoisomers were evaluated in guinea-pig tracheal smooth muscle. 5(S)6(R) LTD4 was 1000 times more potent than histamine as a contractile agent. While a change of the 11-ethylenic bond from cis to trans resulted in a four fold decrease in potency, a change in configuration of the 5-hydroxyl group and/or the 6-peptide adduct resulted in a decrease in potency of at least 2 to 3 orders of magnitude. The contractile activity of all LTD4 isomers was inhibited by FPL 55712, whereas indomethacin markedly enhanced the contractile activity of 5(S)6(R) LTD4, but appeared to have less of an effect on the other diastereomers. The results demonstrate the critical nature of configuration of the 5-hydroxyl and the 6-peptide adduct of eicosatetraenoic acid for maintenance of high affinity for receptors.