Structure-function relationships among ryanodine derivatives. Pyridyl ryanodine definitively separates activation potency from high affinity

Ryanodine derivatives are differentially effective on the two limbs of the ryanodine concentration-effect curve. This study comparing ryanodine, ryanodol, and pyridyl ryanedine and nine C₁₀O(eq) esters of them focuses on structure-function relations underlying their differential effectiveness. Ryanodol and pyridyl ryanodine had significantly lower affinities than ryanodine, but their EC(50act) values (concentration of ryanoid that induces one-half of full efficacy), potencies, and efficacies were not diminished in like fashion. Ryanodine and ryanodol were partial agonists, whereas pyridyl ryanodine was a full agonist, having a diminished deactivation potency. C₁₀O(eq) esterifications enhanced affinities and efficacies of the base ryanoids. The C₁₀-O(eq) ester derivatives of ryanodine and pyridyl ryanodine, but not those of ryanodol, lost their capacity to deactivate RyR1s. Thus, affinity differences among ryanoids clearly do not predicate functional differences as regards activation of Ca²⁺ release channels. The pyrrole carboxylate on the C₃ of ryanodine is dispensable to ryanoid activation of Ca²⁺ release channels. Ryanodol lacks this ring, but it nevertheless effects substantial activation. Moreover, its C₁₀-O(eq) esters display full efficacy. The increased ability of all the C₁₀-O(eq) derivatives to release Ca²⁺ from the vesicles strengthens their role in directly impeding deactivation of RyR1, perhaps by interaction with some component within the transmembrane ionic flux pathway.