Is the A-ring lactone of brevetoxin PbTX-3 required for sodium channel orphan receptor binding and activity?

✍ Scribed by Professor Daniel G. Baden; Kathleen S. Rein; Robert E. Gawley; Gerhard Jeglitsch; David J. Adams

• Book ID: 102963606
• Publisher: John Wiley and Sons
• Year: 1994
• Tongue: English
• Weight: 841 KB
• Volume: 2
• Category: Article
• ISSN: 1056-9014
• DOI: 10.1002/nt.2620020410

✦ Synopsis

Brevetoxin PbTx-3 and non-toxic derivative 4 were investigated for their abilities to bind to the specific brevetoxin receptor site on rat brain synaptosomes and to modulate the normal function of voltage-gated sodium channels as determined by patch clamping of cultured neurons. Compounds 4 and 5 are produced from PbTx-3 by opening of the A-ring lactone to the saturated and unsaturated diols using sodium borohydride in ethanol. Natural PbTx-3 exhibited tighter binding to rat brain synaptosomes by at least 3 orders of magnitude as determined by competitive radioligand binding experiments, and was also more effective at activating voltage-gated channels. Patch clamping revealed the 3 orders of magnitude greater potency of PbTx-3 toxin over 5, although each produced delayed sodium channel opening and a pronounced delay in inactivation. Conformational modeling of the Erevetoxin B backbone indicates that the two molecules are identical except for the region of the A-Ring lactone. Thus, we conclude that the brevetoxin PbTx-3 backbone requires electrophilic functionality in the region of the lactone in PbTx-3, and that opening of the ring in 5 is sufficient to substantially reduce both binding and activity.