Baden D G, Rein K S, Gawley R E, Jeglitsch G, Adams D J
Marine and Freshwater Biomedical Sciences Center, RSMAS University of Miami, Florida.
Nat Toxins. 1994;2(4):212-21. doi: 10.1002/nt.2620020410.
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 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.
研究了短裸甲藻毒素PbTx - 3及其无毒衍生物4与大鼠脑突触体上特定短裸甲藻毒素受体位点的结合能力，以及通过对培养神经元进行膜片钳记录来调节电压门控钠通道正常功能的能力。化合物4和5是通过在乙醇中使用硼氢化钠将PbTx - 3的A环内酯开环生成饱和和不饱和二醇而制得的。通过竞争性放射性配体结合实验测定，天然PbTx - 3与大鼠脑突触体的结合更紧密，至少相差3个数量级，并且在激活电压门控通道方面也更有效。膜片钳记录显示，PbTx - 3毒素的效力比5强3个数量级，尽管两者都导致钠通道开放延迟和失活明显延迟。短裸甲藻毒素B主链的构象模型表明，除了A环内酯区域外，这两个分子是相同的。因此，我们得出结论，短裸甲藻毒素PbTx - 3的主链在PbTx - 3内酯区域需要亲电官能团，并且5中该环的开环足以显著降低结合和活性。
