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 language | English (US) |
|---|---|
| Pages (from-to) | 188-194 |
| Number of pages | 7 |
| Journal | Epilepsia |
| Volume | 33 |
| Issue number | 1 |
| State | Published - 1992 |
| Externally published | Yes |
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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 journal › Article
}
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
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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 -