Anti-dipsotropic isoflavones: the potential therapeutic agents for alcohol dependence.
Daidzin is the active principle of Radix puerariae (RP), an herbal remedy that has been used apparently safely and effectively for the treatment of "alcohol addiction" in China for more than a millennium. It has been shown to reduce alcohol consumption in all animal models tested to date. A link between daidzin's capacity to reduce alcohol consumption and its ability to increase liver mitochondrial monoamine oxidase (MAO): aldehyde dehydrogenase (ALDH-2) activity ratio has been established. Daidzin analogs that potently inhibit ALDH-2 but not MAO are the most anti-dipsotropic, whereas those that also inhibit MAO are not. On the basis of these findings, it was proposed that the liver mitochondrial MAO-ALDH-2 pathway is the primary site of action of daidzin and that a biogenic aldehyde derived from the action of MAO mediates its anti-dipsotropic action. Therefore, to design and synthesize more potent anti-dipsotropic analogs, structural features that would enhance ALDH-2 inhibition and/or decrease MAO inhibition needed to be evaluated. Structure-activity-relationship (SAR) studies have revealed that a sufficient set of criteria for a potent anti-dipsotropic analog is an isoflavone with a free 4'-OH function and a straight-chain alkyl at the 7 position that has a terminal polar function such as -OH, -COOH, or -NH2. The preferable chain lengths for the 7-O-omega-carboxy, 7-O-omega-hydroxy, and 7-O-omega-amino substituents are 5 < or = n < or = 10, 2 < or = n < or = 6, and n > or = 4, respectively. Analogs that meet these criteria have increased potency for ALDH-2 inhibition and/or decreased potency for MAO inhibition and are, therefore, likely to be potent anti-dipsotropic agents.
Keung
Wing Ming
WM
Department of Psychiatry, Massachusetts Mental Health Center, and Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, One Kendall Square, Building 600, Cambridge, Massachusetts 02139, USA. wingming_keung@hms.harvard.edu
D000427:Alcohol Deterrents / Q000494:pharmacology / Q000627:therapeutic use*; D000428:Alcohol Drinking; D000437:Alcoholism / Q000175:diagnosis / Q000188:drug therapy*; D017277:Drug Approval; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012720:Severity of Illness Index; D014481:United States; D014486:United States Food and Drug Administration
D000427:Alcohol Deterrents; D007529:Isoflavones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase