Anticonvulsant activity of the low-affinity uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI): Comparison with the structural analogs dizocilpine (MK-801) and carbamazepine

TY - JOUR

T1 - Anticonvulsant activity of the low-affinity uncompetitive N-methyl-D-aspartate antagonist (±)-5-aminocarbonyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI)

T2 - Comparison with the structural analogs dizocilpine (MK-801) and carbamazepine

AU - Rogawski, Michael A

AU - Yamaguchi, S. I.

AU - Jones, S. M.

AU - Rice, K. C.

AU - Thurkauf, A.

AU - Monn, J. A.

PY - 1991

Y1 - 1991

N2 - (±)-5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (ADCI), a tricyclic compound structurally related to dizocilpine (MK-801) and carbamazepine, was a potent anticonvulsant in the mouse maximal electroshock seizure test when administered i.p. (ED50, 8.9 mg/kg) or p.o. (ED50, 23.5 mg/kg), but failed to cause motor impairment except at substantially higher doses (TD50 values, 49.2 mg/kg i.p. and 293 mg/kg p.o.). ADCI was also protective against chemically induced seizures in mice, including those produced by 4-aminopyridine (ED50, 7.1 mg/kg s.c.) and pentylenetetrazol (ED50, 37.4 mg/kg s.c.). In addition, ADCI antagonized the behavioral effects and lethality of s.c. administered N-methyl-D-aspartate (NMDA; ED50, 15.2 mg/kg), but was a weaker antagonist of kainate-induced clonic seizures (ED50, 33.0 mg/kg), indicating that the drug is a selective functional NMDA antagonist. In common with other NMDA antagonists, ADCI retarded the development of amygdaloid kindled seizures in rats, but failed to attenuate the afterdischarge duration in fully kindled animals. Whole cell voltage clamp recordings from cultured hippocampal neurons demonstrated that ADCI selectively blocks inward current responses to NMDA in a use-dependent fashion without affecting responses to kainate or quisqualate, indicating that ADCI is a selective open channel (uncompetitive) blocker of the NMDA receptor-ionophore complex. ADCI blocked NMDA-evoked inward current responses with a potency (IC50, 14 μM) similar to that with which it displaces [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to NMDA receptor channels in rat brain homogenates (IC50, 11.3 μM). In contrast, dizocilpine (MK-801) was a high potency antagonist of NMDA responses (IC50 ~ 10 nM) whereas carbamazepine only minimally affected NMDA responses even at high concentrations (IC50 > 300 μM). We conclude that ADCI is a low-affinity uncompetitive NMDA antagonist which, like other NMDA antagonists, has a broad spectrum of anticonvulsant activity in animal seizure models. However, in contrast to conventional (high affinity) NMDA antagonists whose propensity to cause neurological side effects may limit their therapeutic usefulness, ADCI has a therapeutic index [maximal electroshock ED50/TD50, 5.5 (i.p.) or 12.5 (p.o.) in the mouse] comparable to that of the widely used antiepileptic drug carbamazepine.

AB - (±)-5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine (ADCI), a tricyclic compound structurally related to dizocilpine (MK-801) and carbamazepine, was a potent anticonvulsant in the mouse maximal electroshock seizure test when administered i.p. (ED50, 8.9 mg/kg) or p.o. (ED50, 23.5 mg/kg), but failed to cause motor impairment except at substantially higher doses (TD50 values, 49.2 mg/kg i.p. and 293 mg/kg p.o.). ADCI was also protective against chemically induced seizures in mice, including those produced by 4-aminopyridine (ED50, 7.1 mg/kg s.c.) and pentylenetetrazol (ED50, 37.4 mg/kg s.c.). In addition, ADCI antagonized the behavioral effects and lethality of s.c. administered N-methyl-D-aspartate (NMDA; ED50, 15.2 mg/kg), but was a weaker antagonist of kainate-induced clonic seizures (ED50, 33.0 mg/kg), indicating that the drug is a selective functional NMDA antagonist. In common with other NMDA antagonists, ADCI retarded the development of amygdaloid kindled seizures in rats, but failed to attenuate the afterdischarge duration in fully kindled animals. Whole cell voltage clamp recordings from cultured hippocampal neurons demonstrated that ADCI selectively blocks inward current responses to NMDA in a use-dependent fashion without affecting responses to kainate or quisqualate, indicating that ADCI is a selective open channel (uncompetitive) blocker of the NMDA receptor-ionophore complex. ADCI blocked NMDA-evoked inward current responses with a potency (IC50, 14 μM) similar to that with which it displaces [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to NMDA receptor channels in rat brain homogenates (IC50, 11.3 μM). In contrast, dizocilpine (MK-801) was a high potency antagonist of NMDA responses (IC50 ~ 10 nM) whereas carbamazepine only minimally affected NMDA responses even at high concentrations (IC50 > 300 μM). We conclude that ADCI is a low-affinity uncompetitive NMDA antagonist which, like other NMDA antagonists, has a broad spectrum of anticonvulsant activity in animal seizure models. However, in contrast to conventional (high affinity) NMDA antagonists whose propensity to cause neurological side effects may limit their therapeutic usefulness, ADCI has a therapeutic index [maximal electroshock ED50/TD50, 5.5 (i.p.) or 12.5 (p.o.) in the mouse] comparable to that of the widely used antiepileptic drug carbamazepine.

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M3 - Article

C2 - 1920122

AN - SCOPUS:0025840423

VL - 259

SP - 30

EP - 37

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -