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

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Abstract
Brevetoxin PbTx‐3 and non‐toxic derivative 4 were investisated for their abilities to bind to the specific brevetoxin receptor site on rat brain synaptosomes and to modulate the normal function of voltase‐sated sodium channels as determined by patch clampins 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 Brevetoxin 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. copy; 1994 Wiley‐Liss, Inc.