The antihypertensive and positive inotropic diterpene forskolin: effects of structural modifications on its activity

Four naturally occurring analogues of forskolin were isolated. Forty-nine semisynthetic derivatives were prepared, incorporating structural alterations at the 1-, 6-, 7-, 9-, 11-, and 14/15-positions. Blood pressure lowering properties of 53 compounds were assessed in anesthetized normotensive cats and of 31 compounds in conscious spontaneously hypertensive (SH) rats. The positive inotropic properties of 25 compounds were investigated in an isolated guinea pig atrial preparation. Forskolin was unique among the compounds in its hypotensive activity in cats and in its positive inotropic properties. Although several derivatives displayed oral antihypertensive activity in the SH rats, none was significantly more potent than forskolin. The optimal structural requirements for activity are apparent, since they are found in forskolin itself.