PubMed · 11918954
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Colin Brewer. 2002-03-16. The deterrence issue.. https://doi.org/10.1016/s0140-6736(02)08011-x
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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.
The family doctor plays an important role in the treatment of alcoholism, especially in the initial contact and motivation phases, but also in the aftercare phase following outpatient or inpatient detoxification and rehabilitation. The central tasks are the diagnosis of alcohol dependency and possible neurological and somatic sequelae, mediation, information about consequences and motivation to undergo further treatment. After successful treatment (abstinence)--prevention of relapse, where necessary using so-called anti-craving drugs such as acamprostate.
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.