Preclinical evaluation of PNU-151774E as a novel anticonvulsant.

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 MAOB 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.

• Authors: 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, C Post
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 285 Issue 2 Pg. 397-403 (May 1998) ISSN: 0022-3565 [Print] United States
• PMID: 9580576 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Benzylamines
• safinamide
• Alanine

Topics

• Alanine (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology)
• Animals
• Anticonvulsants (adverse effects, pharmacokinetics, pharmacology)
• Avoidance Learning (drug effects)
• Benzylamines (adverse effects, pharmacokinetics, pharmacology)
• Drug Tolerance
• Male
• Mice
• Mice, Inbred ICR
• Motor Activity (drug effects)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar