title: Novel medication targets for the treatment of alcoholism: preclinical studies.
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.
authors.affiliation: Dept. of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Azadi@duke.edu
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.forename: Maria P
authors.initials: MP
authors.lastname: Arolfo
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: David H
authors.initials: DH
authors.lastname: Overstreet
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology* / Q000627:therapeutic use; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000523:psychology*; D015507:Drugs, Investigational / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods*; D010330:Patents as Topic; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C559587:(4-cyclobutyl-(1,4)diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone; D000427:Alcohol Deterrents; D001381:Azepines; D001384:Azetidines; C550386:CVT-10216; D002219:Carbamates; D015507:Drugs, Investigational; D007529:Isoflavones; C517656:JNJ-5234801; D010880:Piperidines; D011725:Pyridines; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; C514816:sazetidine-A