FORSKOLIN DERIVATIVES .1. SYNTHESIS, AND CARDIOVASCULAR AND ADENYLATECYCLASE-STIMULATING ACTIVITIES OF WATER-SOLUBLE FORSKOLINS

Water-soluble forskolin and 7-deacetylforskolin derivatives with an am inoacetyl, a 3-aminopropionyl, or a 4-aminobutyryl group at the 6- or 7-position were prepared, and their positive inotropic as well as vaso dilative activities were evaluated in anesthetized dogs, 7-Deacetytfor skolin (2) and 7-deacetyl-1-silylforskolin (6) were converted to the c orresponding 7-chloroacylderivatives (3, 7, 10), which were reacted wi th amines to obtain 7-aminoacyl-7-deacetylforskolins (4a-f, 9a, b, 11) , The 7-acyl substituents migrated to the 6-position with sodium hydro xide in acetonitrile-water to afford 6-aminoacyl-7-deacetylforskolins (12a-f). The 7-position of 12a, d-f was selectively acetylated with ac etyl chloride to obtain the corresponding 6-aminoacylforskolins (13a-d ). Among the 6-aminoacylforskolins, 6-(3-dimethylaminopropionyl)forsko lin (13b) and 6-(4-dimethylaminobutyryl)forskolin (13d) exhibited pote nt positive inotropic and vasodilative activities comparable to those of forskolin (I), The activities of 13b and 13d were approximately ten times more potent than those of 7-aminoacyl- and 6-aminoacyl-7-deacet ylforskolins (4a-f, 9a, 12a-c,f). 6-Dimethylaminoacetylforskolin (13a) adn 6-(3-diethylaminopropionyl) (13c) were less potent than 1, The ef fects of the soluble forskolins on adenylate cyclase activity were als o examined in vitro. 6-Aminoacylforskolins (13a-d) exhibited potent ad enylate cyclase-stimulating activity, comparable to that of 1.