Characterization of Non-Nitrocatechol Pan and Isoform Specific Catechol-O-methyltransferase Inhibitors and Substrates
| Autor: | Ronald G. Robinson, Kausik K. Nanda, B. Wesley Trotter, Pete H. Hutson, Monika Kandebo, James Mulhearn, Debra McLoughlin, Sean M. Smith, Stacey L. Polsky-Fisher, Tiffany L. Walker, Jennifer L. Kershner, Peter J. Manley, Neetesh Bhandari, Nancy A. Sachs, James C. Barrow, Dawn L. Hall, Zhijian Zhao, Scott T. Harrison, Lihang Yao, Robert F. Smith, John M. Sanders, Christopher R. Gibson, Sujata Sharma, Jeffrey W. Schubert, Scott E. Wolkenberg |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Physiology Dopamine Cognitive Neuroscience Metabolite Blotting Western Pharmacology Catechol O-Methyltransferase behavioral disciplines and activities Biochemistry Substrate Specificity Nitrophenols Rats Sprague-Dawley Benzophenones chemistry.chemical_compound mental disorders medicine Animals Humans Entacapone Enzyme Inhibitors Rats Wistar Prefrontal cortex Membrane Potential Mitochondrial Catechol-O-methyl transferase Tolcapone Chemistry Cell Membrane fungi Homovanillic acid Catechol O-Methyltransferase Inhibitors Cell Biology General Medicine Human brain Matrix Metalloproteinases Recombinant Proteins Rats Isoenzymes medicine.anatomical_structure nervous system Schizophrenia Biomarkers Antipsychotic Agents medicine.drug |
| Zdroj: | ACS Chemical Neuroscience. 3:129-140 |
| ISSN: | 1948-7193 |
| Popis: | Reduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since membrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial membrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity. |
| Databáze: | OpenAIRE |
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