Khalil Ashraf A, Davies Bruce, Castagnoli Neal
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061-0212, USA.
Bioorg Med Chem. 2006 May 15;14(10):3392-8. doi: 10.1016/j.bmc.2005.12.057. Epub 2006 Feb 3.
It is well established that tobacco smokers have reduced levels of monoamine oxidase activities both in the brain and peripheral organs. Furthermore, extensive evidence suggests that smokers are less prone to develop Parkinson's disease. These facts, plus the observation that inhibition of monoamine oxidase B protects against the parkinsonian inducing effects of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have prompted studies to identify monoamine oxidase inhibitors in the tobacco plant and tobacco cigarette smoke. Our previous efforts on cured tobacco leaf extracts have led to the characterization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-selective monoamine oxidase inhibitor, and farnesylacetone, a selective monoamine oxidase B inhibitor. We now have extended these studies to tobacco smoke constituents. Fractionation of the smoke extracts has confirmed and extended the qualitative results of an earlier report [J. Korean Soc. Tob. Sci.1997, 19, 136] demonstrating the inhibitory activity of the terpene trans,trans-farnesol on rat brain MAO-B. In the present study, K(i) values for the inhibition of human, baboon, monkey, dog, rat, and mouse liver MAO-B have been determined. Noteworthy is the absence of inhibitory effects on human placental MAO-A and beef liver MAO-B. A limited structure-activity relationship study of analogs of trans,trans-farnesol is reported. Although the health hazards associated with the use of tobacco products preclude any therapeutic opportunities linked to smoking, these results suggest the possibility of identifying novel structures of compounds that could lead to the development of neuroprotective agents.
众所周知，吸烟者大脑和外周器官中的单胺氧化酶活性水平降低。此外，大量证据表明吸烟者患帕金森病的可能性较小。这些事实，再加上单胺氧化酶B的抑制作用可预防黑质纹状体神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的帕金森病效应这一观察结果，促使人们开展研究以鉴定烟草植物和烟草烟雾中的单胺氧化酶抑制剂。我们之前对烤烟叶提取物的研究已鉴定出一种非选择性单胺氧化酶抑制剂2,3,6-三甲基-1,4-萘醌以及一种选择性单胺氧化酶B抑制剂法尼基丙酮。我们现在已将这些研究扩展至烟草烟雾成分。烟雾提取物的分级分离证实并扩展了一份早期报告[《韩国烟草科学学会杂志》1997年，第19卷，第136页]的定性结果，该报告表明萜烯反式，反式-法尼醇对大鼠脑MAO-B具有抑制活性。在本研究中，已测定了反式，反式-法尼醇对人、狒狒、猴、狗、大鼠和小鼠肝脏MAO-B抑制作用的K(i)值。值得注意的是，其对人胎盘MAO-A和牛肝MAO-B没有抑制作用。本文报道了反式，反式-法尼醇类似物的有限构效关系研究。尽管使用烟草制品带来的健康危害排除了与吸烟相关的任何治疗机会，但这些结果表明有可能鉴定出可导致开发神经保护剂的新型化合物结构。
