title: Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates.
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.
authors.affiliation: Psychiatric Research, Merck Sharp & Dohme Corp., West Point, Pennsylvania, USA. ron_robinson@merck.com
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.forename: Scott E
authors.initials: SE
authors.lastname: Wolkenberg
authors.forename: Monika
authors.initials: M
authors.lastname: Kandebo
authors.forename: Lihang
authors.initials: L
authors.lastname: Yao
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Gibson
authors.forename: Scott T
authors.initials: ST
authors.lastname: Harrison
authors.forename: Stacey
authors.initials: S
authors.lastname: Polsky-Fisher
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Manley
authors.forename: James J
authors.initials: JJ
authors.lastname: Mulhearn
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Schubert
authors.forename: B Wesley
authors.initials: BW
authors.lastname: Trotter
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhao
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Robert F
authors.initials: RF
authors.lastname: Smith
authors.forename: Debra
authors.initials: D
authors.lastname: McLoughlin
authors.forename: Sujata
authors.initials: S
authors.lastname: Sharma
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Hall
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Walker
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Kershner
authors.forename: Neetesh
authors.initials: N
authors.lastname: Bhandari
authors.forename: Pete H
authors.initials: PH
authors.lastname: Hutson
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Sachs
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology; D015415:Biomarkers; D015153:Blotting, Western; D002394:Catechol O-Methyltransferase / Q000302:isolation & purification / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry; D012559:Schizophrenia / Q000188:drug therapy; D013379:Substrate Specificity; D000077867:Tolcapone
chemical_list: D014150:Antipsychotic Agents; D001577:Benzophenones; D015415:Biomarkers; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009596:Nitrophenols; D011994:Recombinant Proteins; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; D020782:Matrix Metalloproteinases; D004298:Dopamine