Brevetoxin derivatives that inhibit toxin activity

Background: The brevetoxins are marine neurotoxins that interfere with the normal functions of the voltage-gated Na⁺ channel. We have identified two brevetoxin derivatives that do not exhibit pharmacological properties typical of the brevetoxins and that function as brevetoxin antagonists. Results: PbTx-3 and benzoyl-PbTx-3 elicited Na⁺ channel openings during steady-state depolarizations; however, two PbTx-3 derivatives retained their ability to bind to the receptor, but did not elicit Na⁺ channel openings. α-Naphthoyl-PbTx-3 acted as a PbTx-3 antagonist but did not affect Na⁺ channels that were not exposed to PbTx-3. β-Naphthoyl-PbTx-3 reduced openings of Na⁺ channels that were not exposed to PbTx-3. Conclusions: Some modifications to the brevetoxin molecule do not alter either the binding properties or the activity of these toxins. Larger modifications to the K-ring sidechain do not interfere with binding but have profound effects on their pharmacological properties. This implies a critical function for the K-ring sidechain of the native toxin.