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J Biol Chem, Vol. 273, Issue 20, 12176-12186, May 15, 1998

Structure-Function Relationships among Ryanodine Derivatives
PYRIDYL RYANODINE DEFINITIVELY SEPARATES ACTIVATION POTENCY FROM HIGH AFFINITY

From the Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120

Ryanodine derivatives are differentially effective on the two limbs of the ryanodine concentration-effect curve. This study comparing ryanodine, ryanodol, and pyridyl ryanodine 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.

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