Relationship between structure, positive inotropic potency and lethal dose of grayanotoxins in guinea pig.

Relationship between chemical structure, positive inotropic potency and lethal dose of grayanotoxins and the related compounds was studied using guinea pigs. The positive inotropic effect (PIE) was examined in their papillary muscle isolated from the heart. The potency of these compounds was expressed by pD2 values, and was determined by depicting the concentration-PIE curve for each compound. The study has clarified the contribution of functional groups in the molecule; the presence of 3 beta-hydroxyl, 6 beta-hydroxyl and 10 beta-methyl groups attached to the grayanane skeleton is established to be essential for the development of PIE. The inotropic potency of compounds carrying these essential groups is increased by a 10 alpha-hydroxyl group and the acylation of the 14 beta-hydroxyl group. LD50 value of 10 compounds with a high cardiotonic potency (pD2 greater than 4) was determined by up and down method using male guinea pigs. The relation of LD50 to pD2 bore a significant correlation (r = 0.68, p less than 0.05). The most cardiotropic and toxic compound found in this study was asebotoxin III.