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.
(+-)-5-Aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] [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 microM) 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 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Rogawski
M A
MA
Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Yamaguchi
S
S
Jones
S M
SM
Rice
K C
KC
Thurkauf
A
A
Monn
J A
JA
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000517:prevention & control*; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; C071316:5-aminocarbonyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine; D002220:Carbamazepine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate