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

S. M. Jones, Michael A Rogawski

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)303-310
Number of pages8
JournalMolecular Neuropharmacology
Volume2
Issue number4
StatePublished - 1992
Externally publishedYes

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Imines
Dizocilpine Maleate
N-Methylaspartate
Anticonvulsants
Neurons
Inhibitory Concentration 50
Quisqualic Acid
Kainic Acid
Carbamazepine
Patch-Clamp Techniques
5-aminocarbonyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine
Seizures
Animal Models

ASJC Scopus subject areas

  • Neuroscience(all)
  • Pharmacology

Cite this

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title = "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",
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.",
author = "Jones, {S. M.} and Rogawski, {Michael A}",
year = "1992",
language = "English (US)",
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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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