O'Neill M J, Murray T K, McCarty D R, Hicks C A, Dell C P, Patrick K E, Ward M A, Osborne D J, Wiernicki T R, Roman C R, Lodge D, Fleisch J H, Singh J
Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK.
Brain Res. 2000 Jul 21;871(2):234-44. doi: 10.1016/s0006-8993(00)02471-9.
In the present studies, we have evaluated the effects of N-[4-(2-¿[(3-Chlorophenyl)methyl]amino¿ethyl)phenyl]-2-thiophenecarbo ximidamide dihydrochloride (ARL 17477) on recombinant human neuronal NOS (nNOS) and endothelial NOS (eNOS). We then carried out pharmacokinetic studies and measured cortical nitric oxide synthase (NOS) inhibition to determine that the compound crossed the blood brain barrier. Finally, the compound was evaluated in a model of global ischaemia in the gerbil and two models of transient focal ischaemia in the rat. The IC(50) values for ARL 17477 on human recombinant human nNOS and eNOS were 1 and 17 microM, respectively. ARL 17477 (50 mg/kg i.p.) produced a significant reduction in the ischaemia-induced hippocampal damage following global ischaemia when administered immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. In the endothelin-1 model of focal ischaemia, ARL 17477 (1 mg/kg i.v.) significantly attenuated the infarct volume when administered at either 0, 1 or 2 h post-endothelin-1 (P<0.05). In the intraluminal suture model, ARL 17477 at both 1 and 3 mg/kg i.v. failed to reduce the infarct volume measured at 1, 3 or 7 days post-occlusion. These results demonstrate that ARL 17477 protects against global ischaemia in gerbils and provides some reduction in infarct volume following transient middle cerebral artery occlusion in rats, indicating that nNOS inhibition may be a useful treatment of ischaemic conditions.
在本研究中，我们评估了N-[4-(2-[(3-氯苯基)甲基]氨基)乙基]苯基]-2-噻吩甲脒二盐酸盐（ARL 17477）对重组人神经元型一氧化氮合酶（nNOS）和内皮型一氧化氮合酶（eNOS）的作用。然后我们进行了药代动力学研究，并测量了皮质一氧化氮合酶（NOS）抑制情况以确定该化合物能够穿过血脑屏障。最后，在沙鼠全脑缺血模型和大鼠两种短暂性局灶性缺血模型中对该化合物进行了评估。ARL 17477对重组人nNOS和eNOS的IC(50)值分别为1 μM和17 μM。在闭塞后立即给予ARL 17477（腹腔注射50 mg/kg）可显著减轻全脑缺血后缺血诱导的海马损伤，但如果给药延迟至闭塞后30分钟则无法起到保护作用。在局灶性缺血的内皮素-1模型中，在给予内皮素-1后0、1或2小时给予ARL 17477（静脉注射1 mg/kg）可显著减小梗死体积（P<0.05）。在管腔内缝合模型中，静脉注射1 mg/kg和3 mg/kg的ARL 17477均未能减小闭塞后1、3或7天测得的梗死体积。这些结果表明，ARL 17477可保护沙鼠免受全脑缺血的影响，并在大鼠短暂性大脑中动脉闭塞后使梗死体积有所减小，这表明抑制nNOS可能是治疗缺血性疾病的一种有效方法。
