(+-)-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)