Forskolin derivatives. I. Synthesis, and cardiovascular and adenylate cyclase-stimulating activities of water-soluble forskolins

Water-soluble forskolin and 7-deacetylforskolin derivatives with an aminoacetyl, a 3-aminopropionyl, or a 4-aminobutyryl group at the 6- or 7-position were prepared, and their positive inotropic as well as vasodilative activities were evaluated in anesthetized dogs. 7-Deacetylforskolin (2) and 7-deacetyl-1-silylforskolin (6) were converted to the corresponding 7-chloroacylderivatives (3, 7, 10), which were reacted with amines to obtain 7-aminoacyl-7-deacetylforskolins (4a-f, 9a, b, 11). The 7-acyl substituents migrated to the 6-position with sodium hydroxide in acetonitrile-water to afford 6-aminoacyl-7-deacetylforskolins (12a-f). The 7-position of 12a, d-f was selectively acetylated with acetyl chloride to obtain the corresponding 6-aminoacylforskolins (13a-d). Among the 6-aminoacylforskolins, 6-(3-dimethylaminopropionyl)forskolin (13b) and 6-(4-dimethylaminobutyryl)forskolin (13d) exhibited potent positive inotropic and vasodilative activities comparable to those of forskolin (1). The activities of 13b and 13d were approximately ten times more potent than those of 7-aminoacyl- and 6-aminoacyl-7-deacetylforskolins (4a-f, 9a, 12a-c, f). 6-Dimethylaminoacetylforskolin (13a) and 6-(3-diethylaminopropionyl)forskolin (13c) were less potent than 1. The effects of the soluble forskolins on adenylate cyclase activity were also examined in vitro. 6-Aminoacylforskolins (13a-d) exhibited potent adenylate cyclase-stimulating activity, comparable to that of 1.