Effects of entacapone and tolcapone on mitochondrial membrane potential

Haasio, Kristiina; Koponen, A; Penttilä, Kai E.; Nissinen, Erkki

doi:10.1016/s0014-2999(02)02383-x

Cited by 73 publications

(54 citation statements)

References 18 publications

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“…Compounds 69 and 70 were evaluated in vitro for their ability to uncouple oxidative phosphorylation, which appears to be one of the most important mechanisms of the cell toxicity caused by some nitrocatechol derivatives, such as 37. 122,123 The presented data confirmed that compounds 69 and systemic clearance. 151 The exact structure of the clinical candidate for the treatment of PD has not been revealed publicly, but it was later reported that the phase I clinical trial was discontinued due to the conclusion that the clinical candidate pharmacological properties would not outperform those of 32 or 37.…”

Section: Fused Nitrocatechol Derivativessupporting

confidence: 81%

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

2014

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Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.

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Section: Fused Nitrocatechol Derivativessupporting

confidence: 81%

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

2014

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“…CNVRs statistically overrepresented in schizophrenia cases and replicated in an independent case-control cohort sential for maintaining mitochondrial genome integrity and mitochondrial autophagy (45,46). Inhibition of COMT results in mitochondrial uncoupling (47). EDEM1 protects the cell from mitochondrial damage from paraquat (48).…”

Section: Discussionmentioning

confidence: 86%

Strong synaptic transmission impact by copy number variations in schizophrenia

Glessner

Reilly

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

208

196

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Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 × 10 −7 ). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.genetics | genomics | neurobiology

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“…Again, it can be surmized that certain drugs, which are used to treat such neurodegenerative diseases (e.g., tolcapone or tacrine) and that themselves are known to potentially impair mitochondrial function (Berson et al, 1996;Robertson et al, 1998;Haasio et al, 2002;Smith et al, 2003), might exacerbate the underlying mitochondrial injury. This could become toxicologically relevant under two conditions; first, in tissues or cells with a high energy demand and a high mitochondrial density, and second, and importantly, in cells which have the capacity to enzymatically bioactivate the drug to a reactive metabolite that is ultimately responsible for the mitochondrial functional damage.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Animal Models of Human Disease in Drug Safety Assessment

Boelsterli

2003

J. Toxicol. Sci.

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-Animal models of human disease have been widely used in drug discovery, but they are rarely utilized in toxicological research and screening (except for transgenic models in carcinogenicity testing). Although genetic and/or acquired pathophysiological alterations associated with a particular disease may greatly exacerbate toxic responses to drugs in certain patient subsets, these pre-existing pathological conditions are usually not considered in preclinical safety assessment. Examples of disease-related determinants of susceptibility include disruption of the cytokine network in pro-inflammatory conditions, mitochondrial alterations and oxidative stress in certain neurodegenerative diseases, altered antioxidant defense in certain viral infections, and altered gene expression and mitochondrial dysfunction in type 2 diabetes. Hence, if cellular stress caused by drugs or metabolites and the disease-related effects are superimposed, then an individual can become sensitized to potential drug toxicity. Animal models of modest inflammation indeed can potentiate the toxicity of certain drugs. Similarly, rodent models of type 2 diabetes predispose the animals to hepatotoxic effects of thiazolidinediones antidiabetics. In conclusion, it is suggested that tailor-made and simplified models be adopted and increasingly used, in spite of clear limitations, as optimal substrates for satellite toxicity studies to facilitate candidate selection, help predict rare and unexpected toxicity, and identify new biomarkers.

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Effects of entacapone and tolcapone on mitochondrial membrane potential

Cited by 73 publications

References 18 publications

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

Strong synaptic transmission impact by copy number variations in schizophrenia

Animal Models of Human Disease in Drug Safety Assessment

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