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Role of Catechol-O-Methyltransferase (COMT)-Dependent Processes in Parkinson’s Disease and L-DOPA Treatment

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Abstract:

One of the most important enzymes in the catecholamine cycle, catecholamine-O-methyltransferase (COMT), plays a critical role in the extracellular metabolism of dopamine and norepinephrine both in the periphery and the central nervous system. COMT has attracted strong interest in regards to its role in dopamine-related pathologies, particularly Parkinson’s disease. There are several mechanisms for the potential involvement of COMT-related processes in the pathophysiology of Parkinson’s disease or the consequences of L-DOPA treatment. COMT-mediated metabolism of LDOPA in the periphery influences brain dopamine levels, while the product of central COMT-mediated dopamine metabolism, 3-methoxytyramine, can affect movement via interaction with Trace Amine-Associated Receptor 1 (TAAR1). COMT inhibitors have a long history of clinical use in the treatment of Parkinson’s disease. Several clinical genetic studies have shown that variants of COMT gene contribute to the manifestations or treatment responses of this disorder. Here, we review the basic molecular mechanisms that could be involved in COMT-dependent processes in Parkinson’s disease, the pharmacological properties of COMT inhibitors used in the treatment of this disorder and the clinical genetic observations involving COMT gene variants as modulators of pathological processes and responses to dopamine replacement therapies used in the treatment of the disorder.

Keywords: 3-methoxytyramine; COMT; COMT Inhibitors; Catechol O Methyl Transferase; Dyskinesia; L-DOPA; Parkinson's disease; TAAR1; entacapone; nebicapone; tolcapone; trace amines

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152712800672436

Affiliations: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Morego 30, Genova, Italy.

Publication date: May 1, 2012

More about this publication?
  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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