Tolcapone is a potent, selective and orally active catechol-O-methyltransferase (COMT) inhibitor with Ki of 30 nM.
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Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Specifically, COMT plays a critical role in the inactivation and metabolism of dopamine and other catechol compounds. The enzyme reduces a catechol molecule in order to prevent genomic damage through DNA adduct formation or via oxygen radicals produced from the redox cycling of catechols. Tolcapone is a potent, reversible inhibitor of COMT and the only available COMT inhibitor that is permeable across the blood-brain barrier with Ki of 30 nM[3]. In HepaRG cells (human cell-line), tolcapone decreased the ATP content with IC50 of 100 ± 15 μM and was cytotoxic with IC50 of 333 ± 45 μM. This suggested that tolcapone's impairment of mitochondrial ATP production might be related to inhibition of enzyme complexes of the electron transport chain and to uncoupling of oxidative phosphorylation. In vivo, SMS-KCNR xenograft models treated orally with 125 mg/kg Tolcapone every 24 h, resulted in a smaller average tumor of 490 ± 310 mm3 compared to control tumors of 1100 ± 450 mm3[4]. The efficacy of tolcapone 200 mg three times daily for 6 months had also been examined in patients with stable Parkinson’s disease (n = 97 - 298), in the longer-term study, the reduction from baseline in the Unified Parkinson’s Disease Rating Scale subscale II score seen with tolcapone was significantly greater than the increase seen with placebo at 6 months (primary endpoint); improvements were maintained after 12 months’ therapy[5].
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VA Northern California Health Care System, Mather, CA
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University of California, Berkeley
Berkeley, California, United States, 94704
UCSF: Ernest Gallo Clinic and Research Center
Emeryville, California, United States, 94591 收起 <<
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VA Northern California Health Care System, Mather, CA
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Sacramento, California, United States, 95655
Contact: Andrew S Kayser, MD PhD 925-372-2059 andrew.kayser@va.gov
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Berkeley, California, United States, 94704
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University of California, Berkeley
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Berkeley, California, United States, 94704
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San Francisco, California, United States, 94109
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Hershey, Pennsylvania, United States, 17033
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Charleston, South Carolina, United States, 29425
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