Gao Guang-Yao, Li Dian-Jun, Keung Wing Ming
Center for Biochemical and Biophysical Science and Medicine and Department of Psychiatry at Massachusetts Mental Health Center, Harvard Medical School, Boston, MA 02115, USA.
Bioorg Med Chem. 2003 Sep 1;11(18):4069-81. doi: 10.1016/s0968-0896(03)00397-3.
Daidzin, the active principle of an herbal remedy for 'alcohol addiction', has been shown to reduce alcohol consumption in all laboratory animals tested to date. Correlation studies using structural analogues of daidzin suggests that it acts by raising the monoamine oxidase (MAO)/mitochondrial aldehyde dehydrogenase (ALDH-2) activity ratio (J. Med. Chem. 2000, 43, 4169). Structure-activity relationship (SAR) studies on the 7-O-substituted analogues of daidzin have revealed structural features important for ALDH-2 and MAO inhibition (J. Med. Chem. 2001, 44, 3320). We here evaluated effects of substitutions at 2, 5, 6, 8, 3' and 4' positions of daidzin on its potencies for ALDH-2 and MAO inhibition. Results show that analogues with 4'-substituents that are small, polar and with hydrogen bonding capacities are most potent ALDH-2 inhibitors, whereas those that are non-polar and with electron withdrawing capacities are potent MAO inhibitors. Analogues with a 5-OH group are less potent ALDH-2 inhibitors but are more potent MAO inhibitors. All the 2-, 6-, 8- and 3'-substituted analogues tested so far do not inhibit ALDH-2 and/or have decreased potencies for MAO inhibition. This, together with the results obtained from previous studies, suggests that a potent antidipsotropic analogue would be a 4',7-disubstituted isoflavone. The 4'-substituent should be small, polar, and with hydrogen bonding capacities such as, -OH and -NH(2); whereas the 7-substituent should be a straight-chain alkyl with a terminal polar function such as -(CH(2))(n)-OH with 2< or =n < or =6, -(CH(2))(n)-COOH with 5< or =n < or =10, or -(CH(2))(n)-NH(2) with n > or =4.
黄豆苷元是一种治疗“酒精成瘾”的草药疗法的活性成分，迄今为止，在所有接受测试的实验动物中，它都能减少酒精摄入量。使用黄豆苷元结构类似物的相关性研究表明，它通过提高单胺氧化酶（MAO）/线粒体乙醛脱氢酶（ALDH-2）活性比来发挥作用（《药物化学杂志》，2000年，第43卷，第4169页）。对黄豆苷元的7-O-取代类似物的构效关系（SAR）研究揭示了对ALDH-2和MAO抑制重要的结构特征（《药物化学杂志》，2001年，第44卷，第3320页）。我们在此评估了黄豆苷元2、5、6、8、3'和4'位取代对其ALDH-2和MAO抑制效力的影响。结果表明，具有小的、极性的且具有氢键结合能力的4'-取代基的类似物是最有效的ALDH-2抑制剂，而那些非极性且具有吸电子能力的类似物是有效的MAO抑制剂。具有5-OH基团的类似物是效力较低的ALDH-2抑制剂，但却是效力较高的MAO抑制剂。到目前为止测试的所有2-、6-、8-和3'-取代类似物均不抑制ALDH-2和/或对MAO抑制的效力降低。这与先前研究获得的结果一起表明，一种有效的抗嗜酒性类似物将是一种4'，7-二取代异黄酮。4'-取代基应该是小的、极性的且具有氢键结合能力，如-OH和-NH(2)；而7-取代基应该是具有末端极性官能团的直链烷基，如-(CH(2))(n)-OH，其中2≤n≤6，-(CH(2))(n)-COOH，其中5≤n≤10，或-(CH(2))(n)-NH(2)，其中n≥4。
