title: 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.affiliation: Department of Neuroscience, Istituti Clinici di Perfezionamento, Milan, Italy.
authors.forename: R G
authors.initials: RG
authors.lastname: Fariello
authors.forename: R A
authors.initials: RA
authors.lastname: McArthur
authors.forename: A
authors.initials: A
authors.lastname: Bonsignori
authors.forename: M A
authors.initials: MA
authors.lastname: Cervini
authors.forename: R
authors.initials: R
authors.lastname: Maj
authors.forename: P
authors.initials: P
authors.lastname: Marrari
authors.forename: P
authors.initials: P
authors.lastname: Pevarello
authors.forename: H H
authors.initials: HH
authors.lastname: Wolf
authors.forename: J W
authors.initials: JW
authors.lastname: Woodhead
authors.forename: H S
authors.initials: HS
authors.lastname: White
authors.forename: M
authors.initials: M
authors.lastname: Varasi
authors.forename: P
authors.initials: P
authors.lastname: Salvati
authors.forename: C
authors.initials: C
authors.lastname: Post
mesh_terms: D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001596:Benzylamines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D000927:Anticonvulsants; D001596:Benzylamines; C092797:safinamide; D000409:Alanine