Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates

Ronald G. Robinson, Sean M. Smith, Scott E. Wolkenberg, Monika Kandebo, Lihang Yao, Christopher R. Gibson, Scott T. Harrison, Stacey Polsky-Fisher, James C. Barrow, Peter J. Manley, James J. Mulhearn, Kausik K. Nanda, Jeffrey W. Schubert, B. Wesley Trotter, Zhijian Zhao, John M. Sanders, Robert F. Smith, Debra McLoughlin, Sujata Sharma, Dawn L. HallTiffany L. Walker, Jennifer L. Kershner, Neetesh Bhandari, Pete H. Hutson, Nancy A. Sachs

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)129-140
Number of pages12
JournalACS Chemical Neuroscience
Volume3
Issue number2
DOIs
StatePublished - Feb 15 2012

Keywords

  • Catechol-O-methyltransferase
  • dihydroxyphenylacetic acid
  • fluorescence polarization and hepatotoxicity
  • high throughput screen
  • homovanillic acid

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Robinson, R. G., Smith, S. M., Wolkenberg, S. E., Kandebo, M., Yao, L., Gibson, C. R., Harrison, S. T., Polsky-Fisher, S., Barrow, J. C., Manley, P. J., Mulhearn, J. J., Nanda, K. K., Schubert, J. W., Trotter, B. W., Zhao, Z., Sanders, J. M., Smith, R. F., McLoughlin, D., Sharma, S., ... Sachs, N. A. (2012). Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates. ACS Chemical Neuroscience, 3(2), 129-140. https://doi.org/10.1021/cn200109w