Active groups of saxitoxin and tetrodotoxin as deduced from actions of saxitoxin analogues on frog muscle and squid axon.

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Abstract
The actions of 3 saxitoxin (STX) analogs were studied on the frog sartorius muscle fiber and the squid giant axon. Neosaxitoxin [neo-STX] is a natural analog, while decarbamylsaxitoxin [decarbamyl-STX] and reduced saxitoxin are synthetic. The maximum dV/dt of the action potential in paired-muscle protocol is reduced by the analogs with relative potencies: STX, tetrodotoxin and, neo-STX (1), decarbamyl-STX (0.2) and reduced-STX (0.01). In constant-current studies on frog muscle fibers and in voltage-clamp studies on squid axons, all 3 analogs block only the Na channel without affecting the K channel. All 3 analogs bind to the same site as does STX in a competitive manner. The active groups in STX are probably the 7,8,9 guanidinium and the C-12 hydroxy groups. The carbamyl group contributes to, but is not essential for, activity. Stereospecific groups in tetrodotoxin (TTX) molecule are the 1,2,3 guanidinium and the C-9, C-10 hydroxy groups; C-4 and C-8 groups are important. A new view is proposed in which STX and TTX can bind to a receptor located in the outside surface of the membrane very close to the orifice of the Na channel.