The toxicity of ryanodine (1) and 9,21-didehydroryanodine (2) (the principal active ingredients of the botanical insecticide ryania) to adult female house Ñies (Musca domestica L.) is attributable to binding to the ryanodine receptor (ryr) and thereby disrupting the Ca2`-release channel. These ryanoids, assayed in house Ñies with piperonyl butoxide (PBO) to suppress cytochrome P450-dependent detoxiÐcation, give injected values of 0É07È0É11 kg g~1, KD 50 injected values of 0É39È0É45 kg g~1 and topical values of 12È LD 50 LD 50 50 kg g~1. They inhibit the [3H]ryanodine binding site of house Ñy and rabbit muscle with
values of 3È10 nM. This study examines the e †ect of structure IC 50 on potency, with 15 variants of the cyclohexane substituents, two 4,6-cyclic boron and two methylated derivatives, and four modiÐcations of the isopropyl and ester substituents. The most e †ective compound examined was 10-deoxy-2 (3) which was more potent than 2 by 2È4-fold on injection and 29-fold applied topically following PBO 0É41 kg g~1). Additional high-potency com-(LD 50 pounds were 10-oxo-1 and the cyclohexane variants with lactam, 21-nor-9-oxo and 21-nor-10-deoxy substituents. Other modiÐcations usually reduced toxicity. The injected knockdown potency of the ester ryanoids was generally related to their e †ectiveness in competing with [3H]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 di †erent 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.