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.
Karst
H
H
Department of Pharmacology, University of Amsterdam, The Netherlands.
Piek
T
T
Van Marle
J
J
Lind
A
A
Van Weeren-Kramer
J
J
D000818:Animals; D001345:Autoradiography; D005971:Glutamates / Q000493:pharmacokinetics / Q000502:physiology; D018698:Glutamic Acid; D006110:Grasshoppers; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials; D009466:Neuromuscular Blocking Agents / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D011073:Polyamines; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000502:physiology; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*; D014862:Wasp Venoms / Q000633:toxicity*
D005971:Glutamates; D007473:Ion Channels; D009466:Neuromuscular Blocking Agents; D011073:Polyamines; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D014862:Wasp Venoms; D018698:Glutamic Acid; C034092:delta-philanthotoxin