Methods and assays useful in the treatment of alcohol dependence or alcohol abuse

Abstract

A method for the treatment of alcohol abuse using daidzin and compounds analogous to daidzin is disclosed. Also disclosed is a method for screening compounds having antidipsotropic activity.

Description

STATEMENT OF RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 09 / 616,718, filed Jul. 14, 2000, which is a divisional of U.S. patent application Ser. No. 09 / 310,614, filed May 12, 1999, now issued as U.S. Pat. No. 6,121,010; which in turn claims priority from U.S. Provisional Application Ser. No. 60 / 085,148, filed May 12, 1998, hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] Embodiments of the present invention relate in general to novel methods useful in the treatment of alcohol dependence or alcohol abuse. Embodiments of the present invention also relate to novel assay systems useful in initial screening of compounds having an antidipsotropic effect. Such compounds are useful in therapeutic methods of reducing alcohol consumption as a treatment for alcohol dependence or alcohol abuse. [0004] 2. Description of Related Art [0005] Alcohol abuse and alcohol dependence ...

AI Technical Summary

Benefits of technology

[0013] Embodiments of the present invention are based on the discovery that the enzyme systems of certain biologically active monoamines, such as serotonin (5-HT) and dopamine (DA) in mammalian tissue, can be inhibited using daidzin or analogous compounds and that the inhibition alters the concentration of substrates that regulate ethanol drinking behavior. More particularly, embodiments of the present invention are directed to inhibiting the oxidation of aldehydes that derive from neurotransmitters such as serotonin and dopamine via monoamine oxidase (MAO). It has been discovered that daidzin and daidzin analogs are effective in increasing the concentration of aldehydes formed during the catabolism of certain neurotransmitters and that the increase in aldehyde concentration attributable to the neurotransmitter enzyme systems is effective in reducing alcohol consumption. Further embodiments of the present invention are directed to novel assay systems based on the neurotransmitter enzyme systems which may be used to screen compounds for their ability to inhibit the formation of certain acid products or raise the concentration of certain aldehyde products as a measure of a candidate compound's ability to reduce alcohol consumption in a mammal including a human. The assays of the present invention based upon the monoamine enzyme systems for serotonin and dopamine provide for the first time a reliable system for quantitatively predicting antidipsotropic activity of candidate compounds as a function of aldehyde accumulation.

[0035] The analogs of daidzin can be used in methods to inhibit the enzyme systems of serotonin and dopamine in a manner to increase concentrations of aldehydes present in the enzyme system or inhibit the formation of corresponding acids present in the enzyme system. Such daidzin analogs are potent and have similar significant in vivo effects on alcohol consumption in animal models. Thus, the daidzin and daidzin analogs are useful in methods of reducing alcohol consumption by inhibiting the enzyme systems of certain monoamines, such as serotonin and dopamine in a manner to increase aldehyde concentrations resulting from the catabolism of the neurotransmitters. In addition, novel assay systems are provided according to the present invention whereby candidate compounds can be screened for their ability to effect the enzyme systems of serotonin or dopamine. It has been discovered that compounds which raise aldehyde concentrations within the serotonin or dopamine enzyme systems are also effective as antidipsotropic agents, i.e. agents which reduce alcohol consumption. According to the present invention, a novel assay system is provided whereby a candidate compound is contacted with a monoamine enzyme system, such as a serotonin or dopamine enzyme system. The novel assay system quantitatively gauges the ability of a candidate compound to reduce alcohol consumption based upon its ability to raise aldehyde concentrations within the serotonin or dopamine enzyme systems. The novel assay systems of the present invention, therefore, avoid unnecessary in vivo screening to determine antidipsotropic activity.

Problems solved by technology

Alcohol abuse and alcohol dependence (i.e., alcoholism) are serious public health problems of modern society.

Alcohol dependence and abuse are very expensive: in economic and medical terms, it will cost the U.S. well over $200 billion in 1991 with no prospect of falling or leveling off.

Both alcohol abuse and dependence arise as a result of different, complex, and as yet incompletely understood processes.

However, the art has not recognized whether isoflavone based compounds such as daidzin or daidzin analogs are capable of interacting with the enzyme systems of neurotransmitters or how such compounds would even come in contact with such enzyme systems given the nature and structure of the isoflavone based compounds.

As such, the art provides no guidance as to whether isoflavone based compounds are chemically capable of interacting with the neurotransmitter enzyme systems, such as where crossing of the blood-brain barrier may be necessary or are capable of having any effect on neurotransmitter enzyme systems, especially in a manner to reduce alcohol consumption or otherwise affect the concentration or efficacy of substrates within the enzyme system that regulate ethanol drinking behavior.

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