Structural aspects of ryanodine action and selectivity

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, a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-04, Vol.30 (4), p.710-716
Main Authors: Waterhouse, Andrew L, Pessah, Issac N, Francini, Alexander O, Casida, John E
Format: Article
Language:English
Subjects:
Alkaloids - pharmacology
Alkylation
Animals
Biological and medical sciences
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Diptera - drug effects
Insecticides - pharmacology
Insecticides - toxicity
Ion Channels - drug effects
Male
Medical sciences
Mice
Molecular Conformation
Muscle Contraction - drug effects
Pesticides, fertilizers and other agrochemicals toxicology
Rabbits
Receptors, Cholinergic - drug effects
Ryanodine - analogs & derivatives
Ryanodine - pharmacology
Ryanodine - toxicity
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum - drug effects
Seizures - chemically induced
Species Specificity
Structure-Activity Relationship
Toxicology
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00387a022