Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones.

The effect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole-cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to differentiate their sites of action. The ability of ICS 205,930 (0.2 microM) to potentiate glycine responses persisted in the presence of concentrations of Zn2+ (5-10 microM) that were saturating for the potentiating effect of this ion. Preincubation with 10 microM Zn2+ before application of glycine plus Zn2+ had an inhibitory effect, which did not result from Zn2+ entry into the neurone, since it persisted with either 10 mM internal EGTA or 10 microM internal Zn2+. To test whether the potentiating effects of ICS 205,930 and Zn2+ interact, both compounds were applied without preincubation. The potentiating effect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn2+, provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes. ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM). ICS 205,930 also retained its potentiating effect in the presence of the anaesthetic propofol (30 90 microM), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance. The anticonvulsant chlormethiazole (50-100 microM) neither potentiated glycine responses nor prevented the effect of ICS 205,930, even though it increased the resting conductance and potentiated GABA(A) responses. The mechanism of action of ICS 205,930 appears to be different from those by which Zn2+, propofol or ethanol potentiate glycine responses.