Anticonvulsant 1-phenylcycloalkylamines: Two analogues with low motor toxicity when orally administered

P. A. Blake, S. Yamaguchi -i., A. Thurkauf, Michael A Rogawski

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

1-Phenylcyclohexylamine (PCA) and its analogues 1-phenylcyclopentylamine (PPA) and 1-(3-fluorophenyl)cyclohexylamine (3-F-PCA) are potent anticonvulsants in the mouse maximal electroshock (MES) seizure test. Unlike the structurally related dissociative anesthetic phencyclidine (PCP), however, which produces motor toxicity at anticonvulsant doses, PCA, PPA, and 3-F-PCA protect against MES seizures at 2.2- to 3.5-fold lower doses than those that cause motor toxicity when administered intraperitoneally (i.p.). In the present study, we evaluated the oral anticonvulsant activity of PCA, PPA, and 3-F-PCA in mice; we also examined 3-F-PCA in rats. All the compounds were orally active in the mouse MES seizure test (ED50 values 14.5, 53.4, and 26.7 mg/kg, respectively). Moreover, 3-F-PCA was especially potent in rats, either when administered i.p. (ED50 0.4 mg/kg vs. 9.4 mg/kg in mice) or orally (ED50 0.8 mg/kg). Surprisingly, however, oral PPA failed to cause motor toxicity in mice even at doses that were many times higher than those that were protective in the MES test (TD50 >300 mg/kg). In rats, 3-F-PCA also showed a strikingly low oral toxicity (TD50 >50 mg/kg) in relation to its potency as an anticonvulsant. Like PCP, PCA analogues block N-methyl-D-aspartate (NMDA)-induced behavioral effects and lethality in mice. Moreover, in vitro studies indicate that the compounds act as uncompetitive antagonists of the NMDA receptor-channel complex. Therefore, their anticonvulsant activity may, at least in part, relate to an interaction with NMDA receptors.

Original languageEnglish (US)
Pages (from-to)188-194
Number of pages7
JournalEpilepsia
Volume33
Issue number1
StatePublished - 1992
Externally publishedYes

Keywords

  • Anticonvulsants
  • Convulsions
  • Glutamate
  • Maximal electroshock
  • N-methyl-D-aspartate
  • Pentylenetetrazol
  • Phencyclidine

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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