The actions of amylobarbitone, thiopentone, methohexitone and methyprylone at voltage-clamped frog end-plates were studied. 2. In the presence of barbiturates the conductance change evoked by an iontophoretic carbachol application was reduced by a prepulse of carbachol. The extra inhibition evoked by a prepulse disappeared exponentially with a time constant of 150-200 ms. 3. Barbiturates produce an increased rate of decay of nerve evoked endplate currents. Tne concentration and voltage dependence of the barbtiruate e.p.c. decay rates tally with the hypothesis that the increased rate of decay is due to block of active receptor-channel complexes by barbiturates with a rate constant of 10(6) M-1S-1. 4. Conductance changes produced by bath applied agonists were depressed by thiopentone, the effect becoming greater the higher the agonist concentration. This effect, and also the observation that the concentration of thiopentone required to depress the bath agonist response is much greater than the apparent dissociation constant for binding to active receptor-channel complexes calculated from kinetic measurements, suggest that the selectivity for binding to open receptor-channel complexes is very high. 5. Methyprylone, which is structurally similar to the barbiturates, is only a weak antagonist and shows no interpulse interaction. It was predicted that methyprylone should produce fast and slow components in the e.p.c. decay, and this prediction was verified. 6. In the presence of barbiturates large iontophoretic carbachol applications produce conductance changes which show fast and slow components. Under these conditions the effects of carbachol prepulses become complex. However the effects are qualitatively consistent with the notion that different components of the response are contributed by channels located at various distances from the iontophoretic pipette tip. 7. All the data agree with a model in which the channel has three stages: closed, open and blocked. Only open channels can block, and blocked channels can only open.
