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 b revetoxin derivatives that do not exhibit pharmacological properties typica l of the brevetoxins and that function as brevetoxin antagonists. Results: PbTx-3 and benzoyl-PbTx-3 elicited Na+ channel openings during ste ady-state depolarizations; however, two PbTx-3 derivatives retained their a bility to bind to the receptor, but did not elicit Na+ channel openings. al pha-Naphthoyl-PbTx-3 acted as a PbTx-3 antagonist but did not affect Na+ ch annels that were not exposed to PbTx-3. beta-Naphthoyl-PbTx-3 reduced openi ngs of Na+ channels that were not exposed to PbTx-3. Conclusions: Some modifications to the brevetoxin molecule do not alter eit her the binding properties or the activity of these toxins. Larger modifica tions to the K-ring sidechain do not interfere with binding but have profou nd effects on their pharmacological properties. This implies a critical fun ction for the K-ring sidechain of the native toxin.