Mediation of the cardiac effects of forskolin by specific binding sites.

The effects of forskolin and seven derivatives on cardiac functions were investigated by using the Langendorff technique and the results compared with the respective potencies obtained from adenylate cyclase and binding studies. In the isolated heart, forskolin increased all parameters measured in the same concentration range as demonstrated by identical EC50 values for increasing contractile force (270 nmol/L), heart rate (276 nmol/L), and coronary flow (249 nmol/L). Compared with its analogs, forskolin was the most potent agonist followed by 7-desacetylforskolin-7-ethylcarbonate, 7-desacetyl-7-propionylforskolin, 14,15-dihydroforskolin, and 7-desacetylforskolin. An identical order of potencies was obtained when these compounds were tested for their ability to inhibit [3H]forskolin binding and stimulate adenylate cyclase in a myocardial preparation. While the KI values derived from the binding experiments (386 nmol/L for forskolin) were similar to the respective EC50 values for the cardiac stimulatory effects, the ED50 values for adenylate cyclase stimulation were about 30-fold higher, e.g., 10 mumol/L for forskolin. Derivatives modified in position 9 of the molecule (1,9-dideoxyforskolin, 9,14-epoxy-15-hydroxyforskolin, and 7-desacetylforskolin-6,7:1,9-dicarbonate) had no effect on the isolated heart nor in adenylate cyclase or binding studies. This identical structure-activity profile observed in the three systems used suggests that the cardiac effects of forskolin are elicited by the one specific binding site described in this study.