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SummarySystemic administration of synthetic PAF produces a number of dose-dependent circulatory effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441, for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate. In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean ± 1 S.D.) 39 ± 5% decrease in carotid blood pressure. Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 ± 8% increase in hematocrit and a 50 ± 11% elevation in bronchial resistance. The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012 mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 μg kg-1 PAF i.v. exhibited 28.7 ±6.5% increase in hematocrit 10 min after injection. The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 pg kg-1 i.v. PAF with a 30 ± 6% increase in hematocrit. Using the primates in a cross-over design, the ED50 OF SRI 63-441 WAS 0.11 MG KG 1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is ∼1:25. The effectiveness of SRI 63-441 in these models suggest potential clinical applications in disease states involving hyperpermeability and pulmonary dysfunction.

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Racemic cyclosativene has been prepared stereospecifically by two routes each involving intramolecular capture of a homoallylic carbonium ion by a carbon-carbon multiple bond. Diels-Alder reaction between propynal and 2,3-dimethylcyclopentadiene followed by suitable elaboration of the product 15 gave the requisite norbornenyl tosylates 23 and 39 possessing endo-substituted alkene and alkyne side chains, respectively. Solvolysis of each in trifluoroethanol afforded tetracyclic products! 25 and 40, contaminated with tricyclic material in the case of 23, demonstrating the superiority of the alkyne group in achieving complete cyclization. The conversions of 25 and 40 to cyclosativene were effected in five and six steps, respectively.