新型五环十一胺神经保护活性的筛选

Screening of novel pentacyclo-undecylamines for neuroprotective activity.

作者信息

Geldenhuys Werner J, Terre'Blanche Gisella, Van der Schyf Cornelis J, Malan Sarel F

机构信息

Department of Pharmaceutical Chemistry, Potchefstroom University for Christian Higher Education, Private Bag X6001, 2531, Potchefstroom, South Africa.

出版信息

Eur J Pharmacol. 2003 Jan 1;458(1-2):73-9. doi: 10.1016/s0014-2999(02)02701-2.

DOI:10.1016/s0014-2999(02)02701-2

PMID:12498909

Abstract

A novel series of pentacyclo-undecylamines with 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane (NGP1-01) as the lead compound was synthesised and screened for neuroprotective activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian mouse model. We hypothesise that these compounds may attenuate excitotoxic neuronal cell death mediated through the NMDA receptor (similar to memantine), and through calcium channel block. The pentacyclo-undecylamines (300 mg/kg) were administered to C57BL/6 mice 30 min before intraperitoneal (i.p.) MPTP administration (35 mg/kg). Striatal dopamine, 3,4-hydroxyphenylacetic acid (DOPAC), and homovanillic acid levels were analysed 10 days later by means of HPLC with electrochemical detection. Increased levels of DOPAC and homovanillic acid were observed when some of the test compounds were administered together with MPTP (compared to animals receiving only MPTP). One compound in the series, 8-phenylethylamino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane, attenuated MPTP-induced striatal dopamine depletion when compared to animals treated with MPTP only (p<0.05).

摘要

以8-苄基氨基-8,11-氧杂五环[5.4.0.0(2,6).0(3,10).0(5,9)]十一烷（NGP1-01）为先导化合物，合成了一系列新型五环十一胺，并在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）帕金森病小鼠模型中筛选其神经保护活性。我们推测这些化合物可能通过N-甲基-D-天冬氨酸受体（类似于美金刚）介导并通过钙通道阻滞减轻兴奋性毒性神经元细胞死亡。在腹腔注射（i.p.）MPTP（35mg/kg）前30分钟，将五环十一胺（300mg/kg）给予C57BL/6小鼠。10天后，通过高效液相色谱-电化学检测分析纹状体多巴胺、3,4-二羟基苯乙酸（DOPAC）和高香草酸水平。当一些受试化合物与MPTP一起给药时，观察到DOPAC和高香草酸水平升高（与仅接受MPTP的动物相比）。该系列中的一种化合物，8-苯乙氨基-8,11-氧杂五环[5.4.0.0(2,6).0(3,10).0(5,9)]十一烷，与仅用MPTP处理的动物相比，减轻了MPTP诱导的纹状体多巴胺耗竭（p<0.05）。