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OtherBEHAVIORAL PHARMACOLOGY

Preclinical Evaluation of PNU-151774E as a Novel Anticonvulsant

R. G. Fariello, R. A. McArthur, A. Bonsignori, M. A. Cervini, R. Maj, P. Marrari, P. Pevarello, H. H. Wolf, J. W. Woodhead, H. S. White, M. Varasi, P. Salvati and C. Post
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 397-403;
R. G. Fariello
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R. A. McArthur
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A. Bonsignori
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M. A. Cervini
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R. Maj
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P. Marrari
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P. Pevarello
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H. H. Wolf
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M. Varasi
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P. Salvati
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C. Post
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Abstract

PNU-151774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a structurally novel anticonvulsant having Na+ channel-blocking and glutamate release-inhibiting properties, as well as being a MAOBinhibitor. Its anticonvulsant activity was evaluated in the maximal electroshock (MES) test and in chemically induced seizures (bicuculline, BIC; picrotoxin, PIC; 3-mercaptopropionic acid, 3-MPA; pentylenetetrazole, PTZ; strychnine, STRYC). Behavioral toxicity was evaluated in the rotorod test with measurements of spontaneous locomotor activity and passive avoidance responding. The anti-MES activity of PNU-151774E in both mice and rats, respectively, produced ED50 values of 4.1 mg/kg and 6.9 mg/kg after i.p. administration or 8.0 mg/kg and 11.8 mg/kg after p.o. administration. Oral anti-MES activity in rats peaked between 1 and 2 h after administration and was evident up to 4 h. This activity was related to brain levels of unchanged drug which peaked at 37 mM within 1 h. Oral ED50 values (mg/kg) effective in blocking tonic extension seizures by chemical convulsants in mice were: BIC (26.9), PIC (60.6), 3-MPA (21.5), STRYC (104.1) and PTZ (26.8). This potency was associated with high therapeutic indices relative to: MES (78.2), BIC (23.3), PIC (10.3), 3-MPA (29.1) and STRYC (6.0). No evidence of tolerance to anti-MES activity after repeated dosing was observed. PNU-151774E did not show anti-absence seizure activity as assessed by i.v. infusion of PTZ. PNU-151774E impaired spontaneous activity in rats only at the oral rotorod ED50 dose of 700 mg/kg p.o. PNU-151774E did not impair passive avoidance responding at doses up to 40 times the oral MES ED50 dose in rats. These results indicate that PNU-151774E is an anticonvulsant effective in various seizure models with a wide therapeutic window, and with a low potential to induce tolerance and locomotor or cognitive side effects.

Footnotes

  • Send reprint requests to: Robert A McArthur, PhD, CNS Discovery Research, 725/209-407, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI, 49007.

  • Abbreviations:
    PNU-151774E
    [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate]
    MES
    maximal electroshock
    BIC
    bicuculline
    PIC
    picrotoxin
    3-MPA
    3-mercaptopropionic acid
    PTZ
    pentylenetetrazole
    STRYC
    strychnine
    AED
    antiepileptic drugs
    CBZ
    carbamazepine
    PHT
    phenytoin
    PB
    phenobarbital
    VPA
    valproate
    DZP
    diazepam
    LTG
    lamotrigine
    TI
    Therapeutic Index
    (+)MK-801 (+)-5-methyl-10
    11-dihydro-5H-dibenzo[a,d]cyclohepten-5–10-imine maleate
    HPLC
    high-performance liquid chromatography
    NIH-NINDS
    National Institutes of Health-National Institute of Neurological Disorders and Stroke
    • Received August 4, 1997.
    • Accepted January 5, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherBEHAVIORAL PHARMACOLOGY

Preclinical Evaluation of PNU-151774E as a Novel Anticonvulsant

R. G. Fariello, R. A. McArthur, A. Bonsignori, M. A. Cervini, R. Maj, P. Marrari, P. Pevarello, H. H. Wolf, J. W. Woodhead, H. S. White, M. Varasi, P. Salvati and C. Post
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 397-403;

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OtherBEHAVIORAL PHARMACOLOGY

Preclinical Evaluation of PNU-151774E as a Novel Anticonvulsant

R. G. Fariello, R. A. McArthur, A. Bonsignori, M. A. Cervini, R. Maj, P. Marrari, P. Pevarello, H. H. Wolf, J. W. Woodhead, H. S. White, M. Varasi, P. Salvati and C. Post
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 397-403;
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