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Rattlesnake poisoning frequently produces a severe tissue damaging effect including myonecrosis and hemorrhage. In this investigation, viriditoxin was isolated from the venom of the prairie rattlesnake (Crotalus viridis viridis), and its chemical properties and biological activities associated with tissue damage were investigated. The toxin has a molecular weight of approximately 115 000 with an isoelectric point of 4.8. Amino acid composition analyses indicate that the toxin consists of approximately 1018 residues with high content of acidic amino acid residues. Circular dichroism was used to examine the conformation of viriditoxin. Although there is some indication of a high beta-sheet content, it is not possible to identify the exact conformation due to the anomalous CD spectra. Viriditoxin has both myotoxic and hemorrhagic activities. High serum creatine kinase activity of mice injected with the toxin substantiates the destructive action of viriditoxin on muscle. Viriditoxin has an LD50 value of approximately 5.0 microgram/g in mice indicating the protein is also moderately lethal in addition to its tissue damaging effect.

Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antogonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD4 than the standard (aerosol route of administration, guinea pig bronchoconstriction model). Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB4 whereas 1 did not. Attempts to establish structure--activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system. All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7. Optical resolution of 7 was achieved by two methods. Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer. Although the enantiomers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC4 and LTD4 when administered by the aerosol route (S antipode 15-fold more potent). The properties of 7 have been compared with several recently reported leukotriene antagonists.