Structural aspects of ryanodine action and selectivity

Andrew L. Waterhouse, Isaac N Pessah, Alexander O. Francini, John E. Casida

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The topography and toxicological relevance of the Ca2+-ryanodine receptor complex are evaluated with ryanodine and two natural analogues (9,21-didehydro and the new 18-hydroxy), 13 ryanoid derivatives (prepared from ryanodine and didehydroryanodine by functionalizing the available pyrrole, olefin, and hydroxyl substituents), and four degradation products. The potency of ryanoids at the skeletal muscle sarcoplasmic reticulum specific binding site generally parallels their toxicity to mice, supporting the toxicological relevance of the Ca2+-ryanodine receptor. The optimal receptor potency of ryanodine and didehydroryanodine is reduced 3-14-fold by hydroxylation at an isopropyl methyl substituent, epimerization at C9, oxidation or acetylation of the C10-hydroxyl, or epoxidation at the 9,21-position; other ryanoids are less active. Ryanodol and didehydroryanodol, in contrast to ryanodine and didehydroryanodine, have low toxicity to mice and little activity at the mammalian receptor, yet they are potent knockdown agents for injected houseflies or cockroaches, suggesting a possible difference in the target sites of mammals and insects.

Original languageEnglish (US)
Pages (from-to)710-716
Number of pages7
JournalJournal of Medicinal Chemistry
Volume30
Issue number4
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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    Waterhouse, A. L., Pessah, I. N., Francini, A. O., & Casida, J. E. (1987). Structural aspects of ryanodine action and selectivity. Journal of Medicinal Chemistry, 30(4), 710-716.