Anti‐dipsotropic isoflavones: The potential therapeutic agents for alcohol dependence

Abstract

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.

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…This condition, termed the alcohol flushing syndrome, commonly occurs in subjects possessing a genetic polymorphism that confers upon them reduced activity of ALDH2, the enzyme responsible for the efficient metabolism of acetaldehyde. This observation led to the initial development of selective ALDH2 inhibitors as antidipsotropic or alcoholaversive agents (Keung, 2003). As our understanding of the roles played by the various ALDH isozymes in disease states continues to expand, the rationale for the development of selective inhibitors of the individual isozymes becomes more apparent.…”

Solubility of daidzin in different organic solvents and (ethyl alcohol+water) mixed solvents

“…Daidzin and daidzein are important members of the isoflavone family and abundant in soybean and Radix Puerariae Lobatae. Daidzin as well as daidzein had attracted much attention due to their many medical effects such as anti-dipsotropic [1] and treatment of alcohol abuse [2]. In order to obtain a high separation efficiency and drug design of daidzin, a knowledge of (solid + liquid) phase equilibrium for daidzin in various solvents is required [3][4].…”

Computer-Aided Modeling of Interaction between Aldehyde Dehydrogenase and Garcinia Biflavonoids

“…Both synthetic and natural ALDH inhibitors have gained significant attention from researchers over the years with the intention of optimally utilizing such inhibitors for the treatment of disease states in which ALDH activity has been implicated in their pathophysiology [40], [41], [42], [43]. ALDHs remain as one of the most characterized proteins till date, and their structure and substrate profiles have been ascertained with exquisite precision [44], [45].…”