Structural aspects of ryanodine action and selectivity

Area of Science:

• Pharmacology
• Toxicology
• Molecular Biology

Background:

• The Ca2+-ryanodine receptor is crucial for calcium release in muscle cells.
• Ryanodine is a known modulator of this receptor, with significant toxicological implications.
• Understanding ryanoid structure-activity relationships is key to assessing their biological effects.

Purpose of the Study:

• To evaluate the topographical and toxicological relevance of the Ca2+-ryanodine receptor complex.
• To investigate the binding affinities and toxicities of ryanodine, its analogues, derivatives, and degradation products.
• To explore potential differences in ryanoid target sites between mammals and insects.

Main Methods:

• Synthesis and characterization of ryanoid derivatives and degradation products.
• Assessment of ryanoid binding affinity to skeletal muscle sarcoplasmic reticulum receptors.
• Evaluation of ryanoid toxicity in mouse models and insect models (houseflies, cockroaches).

Main Results:

• Ryanoid potency at the mammalian Ca2+-ryanodine receptor generally paralleled their toxicity in mice.
• Specific modifications (hydroxylation, epimerization, oxidation, acetylation, epoxidation) reduced optimal receptor potency.
• Ryanodol and didehydroryanodol showed low mammalian receptor activity but potent insecticidal effects, indicating potential target site divergence.

Conclusions:

• The Ca2+-ryanodine receptor is a relevant toxicological target for ryanoids in mammals.
• Structural modifications significantly impact ryanoid potency and toxicity.
• Differences in activity against mammalian and insect targets suggest distinct receptor interactions or sites of action.