Abstract
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) |
|---|---|
| Pages (from-to) | 303-310 |
| Number of pages | 8 |
| Journal | Molecular Neuropharmacology |
| Volume | 2 |
| Issue number | 4 |
| State | Published - 1992 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Neuroscience(all)
- Pharmacology
Cite this
The anticonvulsant (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI) selectively blocks NMDA-activated current in cultured rat hippocampal neurones : Kinetic analysis and comparison with dizocilpine. / Jones, S. M.; Rogawski, Michael A.
In: Molecular Neuropharmacology, Vol. 2, No. 4, 1992, p. 303-310.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The anticonvulsant (±)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI) selectively blocks NMDA-activated current in cultured rat hippocampal neurones
T2 - Kinetic analysis and comparison with dizocilpine
AU - Jones, S. M.
AU - Rogawski, Michael A
PY - 1992
Y1 - 1992
N2 - 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.
AB - 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.
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M3 - Article
AN - SCOPUS:0027104318
VL - 2
SP - 303
EP - 310
JO - Molecular Neuropharmacology
JF - Molecular Neuropharmacology
SN - 0959-5244
IS - 4
ER -