In order to investigate the relationship between the chemical structures and the biological activities of proscillaridin (1) and related compounds, transformations of the lactone (1) into the lactams (2a-i) with monoalkylamines, into 1, 4-cycloadducts (3, 5) with dimethyl acetylenedicarboxylate, and into epoxides (6-8) with tris(acetylacetonate)iron(III)-H₂O₂ have been under-taken. Further, alkoxyalkylation of the teriary C_14β-hydroxy group was carried out with alkoxyalkyl halides. The biological activities of the resulting proscillaridin derivatives were studied by the use of isolated guinea-pig papillary muscle preparations and an Na⁺, K⁺-adenosine triphosphatase preparation from dog kidney.Although the activities of proscillaridin derivatives were less potent than that of 1, compounds 2a, 2g, 3 and 9 showed slightly expanded concentration ranges of positive inotropic effect development on guinea-pig papillary muscle preparations.A significant correlation was obtained between the van der Waals volumes (V_w) and pIC₅₀ values of 1 and 2a-h (r=-0.09, p<0.01).