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脱氨甲酰氧基石房蛤毒素和脱氨甲酰新石房蛤毒素对青蛙骨骼肌纤维的作用。

Actions of decarbamoyloxysaxitoxin and decarbamoylneosaxitoxin on the frog skeletal muscle fiber.

作者信息

Yang L, Kao C Y, Oshima Y

机构信息

Department of Pharmacology, State University of New York, Brooklyn 11203.

出版信息

Toxicon. 1992 May-Jun;30(5-6):645-52. doi: 10.1016/0041-0101(92)90858-3.

Abstract

Two new analogues of the decarbamoyl series of paralytic shellfish toxins have been isolated through improved HPLC methods. In decarbamoyloxysaxitoxin (doSTX), the -OH function at C-13 of decarbamoylsaxitoxin (dcSTX) is changed to -CH3. In decarbamoylneosaxitoxin (dcneoSTX), the carbomyl side-chain of neosaxitoxin (neoSTX) has been removed. The new analogues were assayed on voltage-clamped frog skeletal muscle fiber for their potency in reducing the sodium current. Compared with neoSTX, the relative potencies of dcneoSTX are: 0.003 (at pH 6.50), 0.004 (pH 7.25), and 0.005 (pH 8.25). The influence of pH on the potency is the same in neoSTX and dcneoSTX. The fractional loss of potency caused by decarbamoylation is much greater in neoSTX than in STX, possibly because of an intramolecular interaction between the N-1 -OH in neoSTX and the -OH on C-13. Compared with STX, the ED50 for reducing INa by doSTX is 618 nM, making its relative potency 0.008 that of STX. Energetically, the decreased potency can be accounted for by the loss of two hydrogen bonds, one at the C-13 -OH of dcSTX, and the other at the amino group in the carbamoyl function of STX. These two groups resemble the C-6 and C-11 -OHs in tetrodotoxin, and probably bind to the same site-points. Thus, the near-identical actions of STX and TTX can be attributed to the common sharing of one ion-pair site and four hydrogen-bonding sites. If glutamate 387 of rat brain sodium channel II were the anionic site which ion-pairs with the 7, 8, 9 guanidinium of STX, then the carbonyl oxygen of asparagin 388 is the hydrogen-acceptor for the C-12 gem-diols.

摘要

通过改进的高效液相色谱法分离出了麻痹性贝类毒素脱氨甲酰系列的两种新类似物。在脱氨甲酰氧基石房蛤毒素(doSTX)中,脱氨甲酰石房蛤毒素(dcSTX)C-13位的-OH官能团被-CH3取代。在脱氨甲酰新石房蛤毒素(dcneoSTX)中,新石房蛤毒素(neoSTX)的甲酰基侧链已被去除。在电压钳制的青蛙骨骼肌纤维上检测了这些新类似物降低钠电流的效力。与neoSTX相比,dcneoSTX的相对效力分别为:0.003(pH 6.50时)、0.004(pH 7.25时)和0.005(pH 8.25时)。pH对效力的影响在neoSTX和dcneoSTX中是相同的。脱氨甲酰化导致的效力分数损失在neoSTX中比在STX中要大得多,这可能是因为neoSTX中N-1位的-OH与C-13位的-OH之间存在分子内相互作用。与STX相比,doSTX降低INa的ED50为618 nM,其相对效力为STX的0.008。从能量角度来看,效力降低可归因于两个氢键的丧失,一个在dcSTX的C-13 -OH处,另一个在STX甲酰基官能团的氨基处。这两个基团类似于河豚毒素中的C-6和C-11 -OHs,可能与相同的位点结合。因此,STX和TTX几乎相同的作用可归因于一个离子对位点和四个氢键位点的共同共享。如果大鼠脑钠通道II的谷氨酸387是与STX的7、8、9位胍基形成离子对的阴离子位点,那么天冬酰胺388的羰基氧就是C-12偕二醇的氢受体。

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