A new approach to the design of novel inhibitors of Na+,K+-ATPase: 17alpha-substituted seco-D 5beta-androstane as cassaine analogues.
A new three-dimensional model for the relative binding mode of cassaine 1 and digitoxigenin 2 at the digitalis receptor site is proposed on the basis of the structural and conformational similarities among 1, 2 and its 14,15-seco analogues 3 and 4. Accordingly, the speculation that also 17alpha-substituted derivatives of the digitalis 5beta,14beta-androstane skeleton could efficiently bind to the Na+,K+-ATPase receptor is put forward and verified through the synthesis of some related compounds. The binding affinity shown by 2-(N,N-dimethylamino)ethyl 3beta, 14-dihydroxy-5beta,14beta-androstane-17alpha-acrylate 6 (IC50 = 5.89 microM) and, much more significantly, by the corresponding 14, 15-seco-14-oxo derivative 9 (IC50 = 0.12 microM) substantiates the new hypothesis and opens new prospects to the design of novel inhibitors of Na+,K+-ATPase as potential positive inotropic compounds.
Departments of Medicinal Chemistry and Cellular Biology, Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3, 20019 Settimo Milanese, Milano, Italy, and S.IN Soluzioni Informatiche, via Salvemini 9, 36100 Vicenza, Italy. mc340@mclink.it
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De Munari
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Barassi
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Cerri
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Fedrizzi
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Gobbini
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Mabilia
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Melloni
D045784:Abietanes; D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism*; D000731:Androstanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004070:Digitalis / Q000737:chemistry; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010946:Plants, Medicinal; D010947:Plants, Toxic; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D045784:Abietanes; D000470:Alkaloids; D000731:Androstanes; D004791:Enzyme Inhibitors; C027082:digitalis receptor; D000254:Sodium-Potassium-Exchanging ATPase; C010696:cassaine