Synthesis of potential antidipsotropic isoflavones: inhibitors of the mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway.
Recently we have shown that daidzin, the major active principle of an ancient herbal treatment for "alcohol addiction", suppresses ethanol intake in alcohol-preferring laboratory animals. Further, we have identified the monoamine oxidase (MAO)-aldehyde dehydrogenase (ALDH-2) pathway of the mitochondria as the potential site of action of daidzin. Daidzin analogues that potently inhibit ALDH-2 but have no or little effect on MAO are most antidipsotropic, whereas those that also inhibit MAO exhibit little, if any, antidipsotropic activity. Therefore, in the design and synthesis of more potent antidipsotropic analogues, structural features important for the inhibition of both ALDH-2 and MAO must be taken into consideration. To gain further information on the structure-activity relationships at the inhibitor binding sites of ALDH-2 and MAO, we prepared 44 analogues of daidzin and determined their potencies for ALDH-2 and MAO inhibition. Results indicate that a sufficient set of criteria for a potent antidipsotropic analogue is an isoflavone with a free 4'-OH function and a straight-chain alkyl substituent at the 7 position that has a terminal polar function such as -OH, -COOH, or -NH(2). The preferable chain lengths for the 7-O-omega-hydroxy, 7-O-omega-carboxy, and 7-O-omega-amino subsitutents are 2 < or = n < or = 6, 5 < or = n < or = 10, and n > or = 4, respectively. Analogues that meet these criteria have increased potency for ALDH-2 inhibition and/or decreased potency for MAO inhibition and therefore are likely to be potent antidipsotropic agents.
Gao
G Y
GY
Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, Boston, MA 02115, USA.
Li
D J
DJ
Keung
W M
WM
D000427:Alcohol Deterrents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007529:Isoflavones / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007529:Isoflavones; D008996:Monoamine Oxidase Inhibitors; C004742:daidzein; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial