Abstract
Five hydrogenated proscillaridins (bufa-4, 20-dienolide (PH21), bufa-4, 20 (22)-dienolide (PH22), 20R-bufa-4-enolide (PH4-R), 20S-bufa-4-enolide (PH4-S), chola-4-enoate (PH4-E)) were prepared semi-synthetically, and their pharmacological effect was studied using guinea pigs. The positive inotropic effect (PIE) was examined in papillary muscles isolated from guinea-pig hearts. These compounds produced PIE, dose-dependently; the Dose-PIE curve was characterized by a faster PIE development than that by the parent compound proscillaridin (PS). The concentrations at which half maximum PIE just developed (pD2) were as follows : PS, 7.4; PH22, 6.2; PH21, 5.8; PH4-R, 5.3; PH4-E, 5.0; and PH4-S, 4.9. The time required to the half maximum effect (T50) at a given concentration of pD2 was measured in min: PS, 33; PH4-E, 22; PH22, 15; PH21, 7; PH4-S, 7; and PH4-R, 2. The speeds of inotropy of these compounds depended on the position of lactone ring reduction, though they have the same lipophilicity (Rm). Concentration-PIE curves of reduced PS-compounds were characterized by a decrease in potency and an increase in efficacy. PH21 and PH4-R produced PIE over wider range of concentrations than those of the other compounds. When PH21 at the dose of 11.9 mg/kg, an equivalent dose of 4.4 times the pD2 values, was administrated intravenously by bolus injection into guinea pigs, no arrhythmias were observed on the ECG. The administration of PH22 at the dose of 5.1 mg/kg (at 4.4 times dose of pD2), however, resulted (in an earlier stage after injection) in ventricular rhythms. These results suggest that PH21 has dose-dependent PIE over a wide range of concentrations.
