Effects of synthetic philanthotoxin-4.3.3 (PTX-4.3.3) and of its eleven structural analogues on glutamatergic transmission in the insect muscle, nicotinic transmission in the insect CNS and glutamatergic transmission in the mammalian CNS, are described. Compared with the insect muscle, the insect CNS is about 100 times less sensitive for most of these toxins and the mammalian CNS about 1000 times less reactive. In general, the relative activities of the analogues are comparable except for one toxin: dideaza-PTX-12, which is hardly active in insects and is the most active blocker of synaptic transmission from the Schaffer collaterals to pyramidal cells in the rat hippocampal slices. Dideaza-PTX-12 is also the most active inhibitor of glutamate uptake. It is concluded that the latter compound may be a prototype of a new class of neuroactive drugs affecting the glutamatergic transmission in the mammalian CNS.
