Structure-activity relationship of philanthotoxins--I. Pre- and postsynaptic inhibition of the locust neuromuscular transmission.

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.