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Structural modifications increase the insecticidal activity of ryanodine

The toxicity of ryanodine (1) and 9,21-didehydroryanodine (2) (the principal active ingredients of the botanical insecticide ryania) to adult female house flies (Musca domestica L.) is attributable to binding to the ryanodine receptor (ryr) and thereby disrupting the Ca 2+ -release channel. These ryanoids, assayed in house flies with piperonyl butoxide (PBO) to suppress cytochrome P450-dependent detoxification, give injected KD 50 values of 0.07-0.11 μg g -1 , injected LD 50 values of 0.39-0.45 μg g -1 and topical LD 50 values of 12-50 μg g -1 . They inhibit the [ 3 H]ryanodine binding site of house fly and rabbit muscle with IC 50 values of 3-10 nM. This study examines the effect of structure on potency, with 15 variants of the cyclohexane substituents, two 4,6-cyclic boron and two methylated derivatives, and four modifications of the isopropyl and ester substituents. The most effective compound examined was 10-deoxy-2 (3) which was more potent than 2 by 2-4-fold on injection and 29-fold applied topically following PBO (LD 50 0.41 μg g -1 ). Additional high-potency compounds were 10-oxo-1 and the cyclohexane variants with lactam, 21-nor-9-oxo and 21-nor-10-deoxy substituents. Other modifications usually reduced toxicity. The injected knockdown potency of the ester ryanoids was generally related to their effectiveness in competing with [ 3 H]ryanodine at the ryr of rabbit skeletal muscle. Two non-ester ryanoids, ryanodol and 9,21-didehydroryanodol, were found to be more toxic than predicted from their potency at the ryr and may therefore act in a different manner such as at a K + channel, as suggested by Usherwood and Vais. Clearly ryanoids are challenging prototypes for a potential new generation of insecticides.