Sixteen structural analogs of leukotrienes C and D were tested for their contractile activities on guinea pig pulmonary parenchymal strip and ileum. The analogs differed from the native structures in the position of either the thioether-linked peptide side chain or the hydroxyl group (or both) or in the number and positions of ethylenic bonds. Analogs in which the thioetherlinked peptide chain was attached other than at the C-6 position had substantial reductions in activity on both smooth muscle preparations, whereas analogs in which the various ethylenic bonds were saturated retained substantial contractile activity in both assays. These observations demonstrate that, although a hydrophobic region ofthe eicosinoid is necessary for contractile activity, the length of this segment is more critical than its precise stereochemistry. Analogs of leukotrienes based on the possibility of parallel biosynthetic routes deriving from 8-, 11-, and 15-hydroperoxyeicosatetraenoic acid as precursors were found to effect a comparatively weak contractile response so that their role as biological agents in this respect seems unlikely.The recent demonstration that the biological activity of slowreacting substance of anaphylaxis represents the combined effects of5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans, 11, 14-cis-eicosatetraenoic acid, leukotriene C (LTC) (1-3), and its 6-sulfidocysteinylglycine (4, 5) and 6-sulfido-cysteine analogs (LTD and LTE, respectively) (6) has been associated with an appreciation of their potency in several biological assay systems. For example, the respective activities of LTC and LTD are 500 and 10,000 times greater on a molar basis than is histamine in effecting a contractile response of the guinea pig pulmonary parenchymal strip and 7Q-250 times greater in effect on guinea pig ileum. The molecular structures of these leukotrienes incorporate a polar region from the eicosinoid carboxyl through the C-6 peptide, with the remainder ofthe molecule being nonpolar. We have previously shown a modest decrement in the contractile effects of these compounds on guinea pig ileum and pulmonary parenchymal strip by alteration of the 11,12 ethylenic bond from the cis to the trans conformation, with a greater loss in activity as the C-6 peptide changes from glutathione to cysteine in LTC, LTD, and LTE, respectively (6). We now report the comparative contractile activities of three types of analogs of LTC and LTD.In the first series, certain of the double bonds of the leukotriene structure were replaced by single bonds, so that the effect of geometrical changes in the hydrophobic C-7 to C-20 region of the leukotrienes could be assessed. The second series of analogs is comprised ofstructures (1, 2, and 3) (Fig. 1), which could result from a leukotriene-like biosynthetic mechanism (7) proceeding not from 5-hydroperoxyeicosatetraenoic acid (5-HPETE), the precursor ofleukotrienes, but from 11-HPETE, 15-HPETE, and 8-HPETE instead. Study of the second series not only allows testing of the possible products of natu...