Anticonvulsant activities of 1-phenylcyclohexylamine and its conformationally restricted analog 1,1,-pentamethylenetetrahydroisoquinoline

Michael A Rogawski, A. Thurkauf, S. I. Yamaguchi, K. C. Rice, A. E. Jacobson, M. V. Mattson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

1-Phenylcyclohexylamine (PCA), an analog of phencyclidine (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. Some of the compounds fialed to displace [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine yet and measurable MES anticonvulsant activity (tetrahydroisoquinoline and benzylamine), indicating that an additional mechanism distinct from blockade of NMDA receptor-channels may contribute to the antiseizure activity of this class of drugs. Of the compounds examined, PM-THIQ showed the highest relative potency in the MES anticonvulsant test compared with its motor toxicity. This drug may serve as a prototype for a new class of PCP-related anticonvulsants that have less motor toxicity than PCP.

Original languageEnglish (US)
Pages (from-to)708-712
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume249
Issue number3
StatePublished - 1989
Externally publishedYes

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Electroshock
Anticonvulsants
tenocyclidine
Seizures
Tetrahydroisoquinolines
N-Methyl-D-Aspartate Receptors
Pharmaceutical Preparations
Toxicity Tests
Phencyclidine
Pentylenetetrazole
Aptitude
N-Methylaspartate
1-phenylcyclohexylamine
1,1-pentamethylenetetrahydroisoquinoline
Motor Activity
Brain

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anticonvulsant activities of 1-phenylcyclohexylamine and its conformationally restricted analog 1,1,-pentamethylenetetrahydroisoquinoline. / Rogawski, Michael A; Thurkauf, A.; Yamaguchi, S. I.; Rice, K. C.; Jacobson, A. E.; Mattson, M. V.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 249, No. 3, 1989, p. 708-712.

Research output: Contribution to journalArticle

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