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 Citations (Scopus)

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

Fingerprint

Anticonvulsants
Electroshock
Seizures
N-Methyl-D-Aspartate Receptors
Dissociative Anesthetics
1-phenylcyclohexylamine
Phencyclidine
N-Methylaspartate

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Anticonvulsant 1-phenylcycloalkylamines : Two analogues with low motor toxicity when orally administered. / Blake, P. A.; Yamaguchi -i., S.; Thurkauf, A.; Rogawski, Michael A.

In: Epilepsia, Vol. 33, No. 1, 1992, p. 188-194.

Research output: Contribution to journalArticle

Blake, P. A. ; Yamaguchi -i., S. ; Thurkauf, A. ; Rogawski, Michael A. / Anticonvulsant 1-phenylcycloalkylamines : Two analogues with low motor toxicity when orally administered. In: Epilepsia. 1992 ; Vol. 33, No. 1. pp. 188-194.
@article{041083fe8d1c409fa148408104c2ab28,
title = "Anticonvulsant 1-phenylcycloalkylamines: Two analogues with low motor toxicity when orally administered",
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.",
keywords = "Anticonvulsants, Convulsions, Glutamate, Maximal electroshock, N-methyl-D-aspartate, Pentylenetetrazol, Phencyclidine",
author = "Blake, {P. A.} and {Yamaguchi -i.}, S. and A. Thurkauf and Rogawski, {Michael A}",
year = "1992",
language = "English (US)",
volume = "33",
pages = "188--194",
journal = "Epilepsia",
issn = "0013-9580",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Anticonvulsant 1-phenylcycloalkylamines

T2 - Two analogues with low motor toxicity when orally administered

AU - Blake, P. A.

AU - Yamaguchi -i., S.

AU - Thurkauf, A.

AU - Rogawski, Michael A

PY - 1992

Y1 - 1992

N2 - 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.

AB - 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.

KW - Anticonvulsants

KW - Convulsions

KW - Glutamate

KW - Maximal electroshock

KW - N-methyl-D-aspartate

KW - Pentylenetetrazol

KW - Phencyclidine

UR - http://www.scopus.com/inward/record.url?scp=0026585416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026585416&partnerID=8YFLogxK

M3 - Article

VL - 33

SP - 188

EP - 194

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 1

ER -