Anticonvulsant activities of 1-phenylcyclohexylamine and its conformationally restricted analog 1,1-pentamethylenetetrahydroisoquinoline.
1-Phenylcyclohexylamine (PCA), an analog of phenyclidine (PCP) in which the piperidine ring is replaced by a primary amino group, and its conformationally restricted analog 1,1-pentamethylenetetrahydroisoquinoline (PM-THIQ) were potent anticonvulsants in the mouse maximal electroshock (MES) seizure test (ED50 values, 7.0 and 14.3 mg/kg, respectively). At higher doses, the drugs caused motor impairment (TD50 values, 16.3 and 43.0 mg/kg) and blocked the behavioral effects and lethality of i.p. injected N-methyl-D-aspartate (NMDA) (ED50 values, 36.3 and 127 mg/kg). The separation in potencies in the MES seizure and motor toxicity tests of PCA and PM-THIQ contrasts with PCP which was equally potent in both tests. Several compounds that were structurally related to PM-THIQ (N-ethyl-PCA, 2-methyl-PCA, N-methyl-PM-THIQ, tetrahydroisoquinoline and benzylamine) also blocked MES seizures and caused motor impairment, but failed to show as great a separation between MES anticonvulsant activity and motor toxicity. None of the compounds protected against seizures induced by the chemoconvulsant pentylenetetrazol at doses that lacked motor toxicity. The drugs were also evaluated for their ability to displace [3H]-1-[1-(2-thienyl)-cyclohexyl]piperidine from binding to high affinity acceptor sites (presumably on NMDA receptor-coupled channels) in rat brain homogenates. The rank order of potencies in the binding assay was similar to that in the behavioral tests, except for 2-methyl-PCA which was behaviorally more potent than expected.(ABSTRACT TRUNCATED AT 250 WORDS)
Rogawski
M A
MA
Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland.
Thurkauf
A
A
Yamaguchi
S
S
Rice
K C
KC
Jacobson
A E
AE
Mattson
M V
MV
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity; D001224:Aspartic Acid / Q000031:analogs & derivatives; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003514:Cyclohexylamines / Q000494:pharmacology* / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D044005:Tetrahydroisoquinolines
D000927:Anticonvulsants; D003514:Cyclohexylamines; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D001224:Aspartic Acid; D016202:N-Methylaspartate; C060038:1,1-pentamethylenetetrahydroisoquinoline; C037320:1-phenylcyclohexylamine; D010622:Phencyclidine