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Usnic acid, a lichen antibiotic, showed low-level activity in the Lewis lung carcinoma test system. In an effort to produce new agents of potential use in the treatment of lung cancer, derivatives of the natural product were synthesized and evaluated with a cytotoxicity assay. Structure--activity analysis of the cytotoxicity data indicated the importance of the lipophilicity and the beta-triketone moiety of usnic acid on cytotoxicity. No significant increases in survival of test animals over controls were shown by any of the synthetic compounds in the P388 leukemia or the Lewis lung carcinoma test systems.

In the inhibition of specific binding of [~:Sl]endothelins (ETs) to membranes from various tissues of rats, guinea pigs, pigs and humans, [Cys ~'-Cyst~]-ET-l( I 1-21 ), IRL 1038, has a much higher affinity for ETa receptors (Ki -6-11 nM) than for ET,., receptors (Ka = 0.4-0.7,a M). In contraction a.~ays, with ET-3 as a stimulant, 3 ,aM IRL 1038 antagonized the ET~ receptor-mediated contraction of guinea pig ileal and tracheal smooth muscle without any significant agonistie activity, but did not effect the ETA receptor-mediated contraction of rat aortic smooth muscle. IRL 1038 is, therefore, considered to be the first antagonist selective to the ETn receptor.

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