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 ancie nt herbal treatment for "alcohol addiction", suppresses ethanol intake in a lcohol-preferring laboratory animals. Further, we have identified the monoa mine oxidase (MAO)-aldehyde dehydrogenase (ALDH-2) pathway of the mitochond ria as the potential site of action of daidzin. Daidzin analogues that pote ntly inhibit ALDH-2 but have no or little effect on MAO are most antidipsot ropic, whereas those that also inhibit MAO exhibit little, if any, antidips otropic activity. Therefore, in the design and synthesis of more potent ant idipsotropic analogues, structural features important for the inhibition of both ALDH-2 and MAO must be taken into consideration. To gain further info rmation on the structure-activity relationships at the inhibitor binding si tes of ALDH-2 and MAO, we prepared 44 analogues of daidzin and determined t heir potencies for ALDH-2 and MAO inhibition. Results indicate that a suffi cient set of criteria for a potent antidipsotropic analogue is an isoflavon e with a free 4 ' -OH function and a straight-chain alkyl substituent at th e 7 position that has a terminal polar function such as -OH, -COOH, or -NH2 . The preferable chain lengths for the 7-O-omega -hydroxy, 7-O-omega -carbo xy, and 7-O-omega -amino subsitutents are 2 less than or equal to n less th an or equal to 6, 5 less than or equal to 5 n less than or equal to 10, and n greater than or equal to 4, respectively. Analogues that meet these crit eria have increased potency for ALDH-2 inhibition and/or decreased potency for MAO inhibition and therefore are likely to be potent antidipsotropic ag ents.