TY - JOUR
T1 - Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates
AU - Robinson, Ronald G.
AU - Smith, Sean M.
AU - Wolkenberg, Scott E.
AU - Kandebo, Monika
AU - Yao, Lihang
AU - Gibson, Christopher R.
AU - Harrison, Scott T.
AU - Polsky-Fisher, Stacey
AU - Barrow, James C.
AU - Manley, Peter J.
AU - Mulhearn, James J.
AU - Nanda, Kausik K.
AU - Schubert, Jeffrey W.
AU - Trotter, B. Wesley
AU - Zhao, Zhijian
AU - Sanders, John M.
AU - Smith, Robert F.
AU - McLoughlin, Debra
AU - Sharma, Sujata
AU - Hall, Dawn L.
AU - Walker, Tiffany L.
AU - Kershner, Jennifer L.
AU - Bhandari, Neetesh
AU - Hutson, Pete H.
AU - Sachs, Nancy A.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - 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.
AB - 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.
KW - Catechol-O-methyltransferase
KW - dihydroxyphenylacetic acid
KW - fluorescence polarization and hepatotoxicity
KW - high throughput screen
KW - homovanillic acid
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UR - http://www.scopus.com/inward/citedby.url?scp=84863116237&partnerID=8YFLogxK
U2 - 10.1021/cn200109w
DO - 10.1021/cn200109w
M3 - Article
C2 - 22860182
AN - SCOPUS:84863116237
SN - 1948-7193
VL - 3
SP - 129
EP - 140
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 2
ER -