Ryanoids are the most potent inhibitors known for the calcium-release channel (ryanodine receptor), and they are also botanical insecticides. Twenty-two new ryanoids are described in which the C-4, C-12 bond is ruptured or replaced with an oxygen bridge and in which substituents at C-4 and C-12 are modified to have a wide range of polarities. They are obtained by nucleophilic additions to the 4,12-seco-4,12-dioxo compounds or diketones prepared from ryanodine and dehydroryanodine by periodate oxidation. Structures of the new compounds are distinguished by changes in NMR chemical shifts of 13C and 1H nuclei in the regions of C-4 and C-12. The new ryanoids are compared with ryanodine as inhibitors of [3H]ryanodine binding using a rabbit muscle sarcoplasmic reticulum preparation alone or with ATP and a mouse brain receptor with ATP. They are also examined as knockdown agents for houseflies pretreated with a cytochrome P450 oxidase inhibitor to suppress detoxification and then injection with the ryanoid. The diketones have very weak binding activity in the receptor assays and very low toxicity to flies. Activity approaching that of ryanodine in both the receptor and fly assays is obtained for ketals with small groups at C-12 and polar substituents such as OH or NHOH at C-4. The oximes range from low to moderate potency. Addition of thiols to the vinyl group of dehydroryanodine gives three thioethers all of low biological activity. With most ryanoids addition of ATP to the muscle system increases its sensitivity to near that found for the brain receptor with ATP; possible exceptions are compounds with phenyl substituents. Activity at the calcium-release channel generally follows housefly toxicity although the hydrazine and hydroxyamine adducts are much weaker than expected perhaps due to dissociation under the assay conditions.