STRUCTURE ACTIVITY RELATIONSHIP OF PHILANTHOTOXINS .1. PRESYNAPTIC AND POSTSYNAPTIC INHIBITION OF THE LOCUST NEUROMUSCULAR-TRANSMISSION
STRUCTURE ACTIVITY RELATIONSHIP OF PHILANTHOTOXINS .1. PRESYNAPTIC AND POSTSYNAPTIC INHIBITION OF THE LOCUST NEUROMUSCULAR-TRANSMISSION
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DOI：
10.1016/0742-8413(91)90236-m
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发表时间：
1991-01-01
影响因子：
3.9
通讯作者：
VANWEERENKRAMER, J
中科院分区：
文献类型：
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作者：
KARST, H;PIEK, T;VANWEERENKRAMER, J
1.与天然毒素一样，合成的delta-philanthotoxin（现在称为PTX-4.3.3）也是蝗虫神经肌肉系统突触后开放离子通道的可逆阻滞剂。它还抑制神经末梢和神经胶质细胞对谷氨酸的高亲和力再摄取.为了研究构效关系，对PTX-4.3.3分子的三个部分进行了改变.这些PTX类似物之一，三氟甲基-PTX-4.3.3，被证明是一种更有效的突触后阻滞剂。此外，与PTX-4.3.3相比，三氟甲基-PTX-4.3.3.6的恢复期延迟。许多PTX类似物在抑制离子电渗诱发的突触后谷氨酸电位方面与PTX-4.3.3等效。然而，通过减少多胺链的长度实现完全失活，此外，二脱氮-PTX-12几乎完全失活，并且用脱酚-PTX-4.3.3.8观察到活性降低。谷氨酸电位的衰减时间常数的降低，通常通过Con A预处理制剂中的开放离子通道阻断剂观察到，在应用后两种类似物期间不受影响。可能这两种毒素作为弱受体拮抗剂。10.谷氨酸再摄取的突触前抑制似乎是PTX-4.3.3的非常特异的性质。仅一种测试的类似物（脱羟基-PTX-4.3.3）表现出这种能力。
1. Like the natural toxin, synthetic delta-philanthotoxin, now called PTX-4.3.3 acts as a reversible postsynaptic open ion-channel blocker of the glutamatergic neuromuscular system of the locust.2. It also inhibits the high-affinity re-uptake of glutamate in the nerve endings and glial cells.3. To study the structure-activity relationship, three parts of the PTX-4.3.3 molecule were changed.4. One of these PTX-analogues, trifluoromethyl-PTX-4.3.3, proved to be a more potent postsynaptic blocker.5. Moreover, compared with PTX-4.3.3 a delayed recovery period is seen with trifluoromethyl-PTX-4.3.3.6. A number of PTX-analogues were equipotent to PTX-4.3.3 regarding the inhibition of iontophoretically evoked, postsynaptic glutamate potentials.7. However, complete inactivation was achieved by reducing the length of the polyamine chain, moreover dideaza-PTX-12 was nearly completely inactive and a reduced activity was seen with dephenol-PTX-4.3.3.8. A decrease of the decay time constant of glutamate potentials, normally seen by open ion-channel blockers in Con A pretreated preparations, was unaffected during application of the latter two analogues.9. Possibly these two toxins act as weak receptor antagonists.10. The presynaptic inhibition of the glutamate re-uptake, seemed to be a very specific property of PTX-4.3.3. Only one of the tested analogues (dehydroxy-PTX-4.3.3) exhibited this capacity.