Novel medication targets for the treatment of alcoholism: Preclinical studies

Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Recent patents on CNS drug discovery 05/2012; 7(2):151-62. DOI: 10.2174/157488912800673182
Source: PubMed

ABSTRACT Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4β2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism.

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Available from: Amir H Rezvani, Sep 28, 2015
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    • "Studies have functionally linked neurotransmitters such as γ-aminobutyric acid (GABA), glutamate, dopamine, serotonin , acetylcholine, neuropeptide Y, or corticotropin-releasing hormone (CRH) and their respective receptor systems to ethanol responses and/or AUD at the basic-science, preclinical, and clinical-research levels. Additionally, reports from patent databases and smaller clinical studies suggest that other novel pharmacotherapeutic strategies for treatment of AUD may be on the horizon (Muller et al. 2014; Rezvani et al. 2012). "
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    ABSTRACT: Alcohol use disorder (AUD) and its sequelae impose a major burden on the public health of the United States, and adequate long-term control of this disorder has not been achieved. Molecular and behavioral basic science research findings are providing the groundwork for understanding the mechanisms underlying AUD and have identified multiple candidate targets for ongoing clinical trials. However, the translation of basic research or clinical findings into improved therapeutic approaches for AUD must become more efficient. Translational research is a multistage process of stream-lining the movement of basic biomedical research findings into clinical research and then to the clinical target populations. This process demands efficient bidirectional communication across basic, applied, and clinical science as well as with clinical practitioners. Ongoing work suggests rapid progress is being made with an evolving translational framework within the alcohol research field. This is helped by multiple interdisciplinary collaborative research structures that have been developed to advance translational work on AUD. Moreover, the integration of systems biology approaches with collaborative clinical studies may yield novel insights for future translational success. Finally, appreciation of genetic variation in pharmacological or behavioral treatment responses and optimal communication from bench to bedside and back may strengthen the success of translational research applications to AUD.
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    ABSTRACT: This paper introduces the Special Section: Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence and provides a summary of patents targeting neurotransmitter systems not covered in the other four chapters. The World Health Organization notes that alcoholic-type drinking results in 2.5 million deaths per year, and these deaths occur to a disproportionately greater extent among adolescents and young adults. Developing a pharmacological treatment targeting alcohol abuse and dependence is complicated by (a) the heterogeneous nature of the disease(s), (b) alcohol affecting multiple neurotransmitter and neuromodulator systems, and (c) alcohol affecting multiple organ systems which in turn influence the function of the central nervous system. Presently, the USA Federal Drug Administration has approved three pharmacotherapies for alcoholism: disulfiram, naltrexone, and acamprosate. This chapter provides a summary of the following systems, which are not covered in the accompanying chapters; alcohol and acetaldehyde metabolism, opioid, glycinergic, GABA-A, neurosteroid, dopaminergic, serotonergic, and endocannabinoid, as well as patents targeting these systems for the treatment of alcoholism. Finally, an overview is presented on the use of pharmacogenetics and pharmacogenomics in tailoring treatments for certain subpopulations of alcoholics, which is expected to continue in the future.
    05/2012; 7(2):93-112. DOI:10.2174/157488912800673155
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    ABSTRACT: The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence.
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