1. The effect of (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (ADCI), a novel anticonvulsant structurally related to dizocilpine (MK-801) and carbamazepine, was examined on responses to N-methyl-D-aspartic acid (NMDA) in cultured rat hippocampal neurones using whole-cell voltage-clamp techniques. 2. ADCI inhibited NMDA-induced current in a use-dependent manner. The IC50 obtained at steady-state was 14 μM. In comparison, the IC50 for dizocilpine was 20 nM. 3. The block produced by ADCI was voltage-dependent, being substantially greater at -60 mV than at + 40 mV. 4. ADCI was ineffective at blocking current induced by quisqualate or kainate. 5. In kinetic experiments, the blocking action of ADCI evolved in fast and slow phases. At the IC50 concentration, the time constants of the two phases were < 1 and 40 s, respectively. In contrast, the block produced by the IC50 concentration of dizocilpine evolved in a single phase with a time constant of 86 s. 6. ADCI protects against seizures in several different animal models, but exhibits much lower motor toxicity than dizocilpine at anticonvulsant doses. The present data indicate that selective blockade of NMDA receptors in vivo may, at least in part, account for the anticonvulsant activity of ADCI. Moreover, we propose that the rapidity of the onset of the block induced by ADCI may contribute to its lower motor toxicity.
|Original language||English (US)|
|Number of pages||8|
|State||Published - 1992|
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