Vol. 285, Issue 2, 397-403, May 1998

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

Department of Neuroscience, Istituti Clinici di Perfezionamento, via Bignami, 1, Milan, Italy and Department of Neurology, T. Jefferson University, Philadelphia, Pennsylvania (R.G.F.), CNS Preclinical Research, Pharmacia & Upjohn S.p.A., I-20014 Nerviano (MI), Italy (R.A.M., A.B., M.A.C., R.M., P.S., C.P.), Pharmacokinetics and Metabolism Pharmacia & Upjohn S.p.A., I-20014 Nerviano (MI), Italy (P.M.), Department of Medicinal Chemistry, Pharmacia & Upjohn S.p.A., I-20014 Nerviano (MI), Italy (P.P., M.V.), and NIH-NINDS Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah (J.W.W., H.S.W.)

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 MAO_B inhibitor. 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.