A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number XI 1 853) active in assays for the detection of antagonists of the endothelin-A (ETA) and endothelin-B (ETB) receptors has been identified. The series includes two novel sclerotiorin analogues, ($S,%a-R)-7-deacetyl-l ,O 8,8,8a-tetrahydro-7-à¬>/?/-sclerotiorin, 1, and its 5-dechloro analogue, 2. It also includes 5-chloroisorotiorin, 6, previously unreported as a natural product, in addition to the major product of these fermentations, (+)-sclerotiorin, 5. Data for the inhibition of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding in the ETAand ETBreceptor assays respectively are reported for this series. Compounds1 and 2 were more selective for the rabbit ETAreceptor than for the rat ETB receptor. The IC50 values for 1 and 2 were 9 and 28/*m respectively in an assay based on binding of ET-1 to rabbit ETAreceptors. In an assay based on the binding of ET-3 to the rat ETBreceptor The endothelins (which exist as three isoforms: ET-1, ET-2 and ET-3) are a family of potent vasoconstricting peptides with a variety of biological activities including bronchoconstriction, positive inotropic and chronotropic effects, mitogenesis and potent renal effects. Endothelins are implicated in several human disease states including hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia and cerebral vasospasm1 "40. Recent results obtained with mice deficient in endothelin-1 suggest that it is essential for normal mouse development and may also play a physiological role in cardiovascular homeostasis5). non-selective receptor, recognising the ET isopeptides with equal affinity, was originally identified as the non-vascular smooth muscle receptor. This receptor is localised on endothelial cells in certain tissues and has been associated with vasodilatory activity, perhaps through the release of the endothelin-derived relaxing factor (EDRF). It has been reported, however, that the ETBreceptor is also localised on vascular smooth muscle and mediates a vasoconstrictor response in certain tissues/species. The use of endothelin receptor antagonists is furthering the understanding of the pathophysiological role of the endothelins17~22).The endothelin antagonists discovered to date from microbial sources are predominantly actinomycete metabolites. These include the ETA receptor specific cyclic pentapeptide BE-18257B from Streptomyces misakiensis23\ the benzarlthraquinones WS009Aand WS009B from a Streptomyces sp.24), and the depsipeptide cochinmicins from a Microbispora sp.2 5) There have been fewer reports of endothelin receptor
A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number XI 1 853) active in assays for the detection of antagonists of the endothelin-A (ETA) and endothelin-B (ETB) receptors has been identified. The series includes two novel sclerotiorin analogues, ($S,%a-R)-7-deacetyl-l ,O 8,8,8a-tetrahydro-7-à¬>/?/-sclerotiorin, 1, and its 5-dechloro analogue, 2. It also includes 5-chloroisorotiorin, 6, previously unreported as a natural product, in addition to the major product of these fermentations, (+)-sclerotiorin, 5. Data for the inhibition of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding in the ETAand ETBreceptor assays respectively are reported for this series. Compounds1 and 2 were more selective for the rabbit ETAreceptor than for the rat ETB receptor. The IC50 values for 1 and 2 were 9 and 28/*m respectively in an assay based on binding of ET-1 to rabbit ETAreceptors. In an assay based on the binding of ET-3 to the rat ETBreceptor compounds 1 and 2 exhibited IC50's of 77 and 172/zm. Members of this series of compounds demonstrated antagonist behavior in a secondary assay based on blockade of ET-1 stimulated arachidonic acid release from rabbit renal artery smoothmuscle cells, whenpresent at concentrations of>30jum. The endothelins (which exist as three isoforms: ET-1, ET-2 and ET-3) are a family of potent vasoconstricting peptides with a variety of biological activities including bronchoconstriction, positive inotropic and chrono-tropic effects, mitogenesis and potent renal effects. Endothelins are implicated in several human disease states including hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia and cerebral vasospasm1 "40. Recent results obtained with mice deficient in endothelin-1 suggest that it is essential for normal mouse development and may also play a physiological role in cardiovascular homeostasis5). Two subtypes of endothelin receptors, classified as ETAand ETBreceptors, have been cloned and charac-terised in mammalian systems6~9). Both receptor sub-types are rhodopsin-like in structure and are coupled to G-proteins. A third endothelin receptor subtype has been cloned from Xenopusdermal melanophores and heart10~11.) although this subtype has not yet been described in mammaliantissues. Vasoconstriction in a wide variety of animal tissues can clearly occur via activation of ETA and/or ETB receptors, depending upon the species and vascular bed 913 under study12~ 16). The ETAreceptor mediates vasocon-striction and mitogenic responses and is widely localised in vascular smooth muscle in most tissues. The ETB, or non-selective receptor, recognising the ET isopeptides with equal affinity, was originally identified as the non-vascular smooth muscle receptor. This receptor is localised on endothelial cells in certain tissues and has been associated with vasodilatory activity, perhaps through the release of the endothelin-derived relaxing factor (EDRF). It has been reported, however, that the ETBreceptor is also localised on vas...
Novel Drimane Sesquiterpene Esters from Aspergillus ustus var. pseudodeflectus with Endothelin Receptor Binding Activity. --(HAYES, M. A.; WRIGLEY, S. K.; CHETLAND, I.; REYNOLDS, E. E.; AINSWORTH, A. M.; RENNO, D. V.; LATIF, M. A.; CHENG, X.-M.; HUPE, D. J.; CHARLTON, P.; DOHERTY, A. M.;
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