Fariello R G, McArthur R A, Bonsignori A, Cervini M A, Maj R, Marrari P, Pevarello P, Wolf H H, Woodhead J W, White H S, Varasi M, Salvati P, Post C
Department of Neuroscience, Istituti Clinici di Perfezionamento, Milan, Italy.
J Pharmacol Exp Ther. 1998 May;285(2):397-403.
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.
PNU-151774E [（S）-（+）-2-（4-（3-氟苄氧基）苄基氨基）丙酰胺，甲磺酸盐]是一种结构新颖的抗惊厥药，具有钠通道阻滞和谷氨酸释放抑制特性，同时也是一种单胺氧化酶B（MAOB）抑制剂。在最大电休克（MES）试验以及化学诱导惊厥（荷包牡丹碱，BIC；印防己毒素，PIC；3-巯基丙酸，3-MPA；戊四氮，PTZ；士的宁，STRYC）试验中对其抗惊厥活性进行了评估。在转棒试验中通过测量自发运动活性和被动回避反应来评估行为毒性。PNU-151774E对小鼠和大鼠的抗MES活性，腹腔注射给药后，ED50值分别为4.1mg/kg和6.9mg/kg；口服给药后，ED50值分别为8.0mg/kg和11.8mg/kg。大鼠口服抗MES活性在给药后1至2小时达到峰值，直至4小时仍很明显。该活性与未变化药物的脑内水平有关，其在1小时内达到37mM的峰值。在小鼠中有效阻断化学惊厥剂引起的强直性伸展惊厥的口服ED50值（mg/kg）为：BIC（26.9）、PIC（60.6）、3-MPA（21.5）、STRYC（104.1）和PTZ（26.8）。相对于MES（78.2）、BIC（23.3）、PIC（10.3）、3-MPA（29.1）和STRYC（6.0），这种效力与高治疗指数相关。重复给药后未观察到对抗MES活性产生耐受性的证据。静脉注射PTZ评估显示，PNU-151774E没有抗失神发作活性。仅在大鼠口服转棒试验ED50剂量700mg/kg时，PNU-151774E才损害大鼠的自发活动。在大鼠中，PNU-151774E在高达口服MES ED50剂量40倍的剂量下不损害被动回避反应。这些结果表明，PNU-151774E是一种在各种癫痫模型中有效的抗惊厥药，具有宽治疗窗，且诱导耐受性以及运动或认知副作用的可能性低。
