Synthesis of daidzin analogues as potential agents for alcohol abuse.
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.
Gao
Guang-Yao
GY
Center for Biochemical and Biophysical Science and Medicine and Department of Psychiatry at Massachusetts Mental Health Center, Harvard Medical School, Boston, MA 02115, USA.
Li
Dian-Jun
DJ
Keung
Wing Ming
WM
D000427:Alcohol Deterrents / Q000138:chemical synthesis* / Q000494:pharmacology; D000437:Alcoholism / Q000517:prevention & control*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D006224:Cricetinae; D066298:In Vitro Techniques; D007529:Isoflavones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000427:Alcohol Deterrents; D007529:Isoflavones; D008996:Monoamine Oxidase Inhibitors; C013908:daidzin; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D008995:Monoamine Oxidase