Optimization of 8-Hydroxyquinolines as Inhibitors of CatecholO-Methyltransferase

Abstract

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray co-crystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.

Development of a PC12 Cell Based Assay for Screening Catechol-O-methyltransferase Inhibitors

“…Enzyme was prepared for these assays as previously reported. 9 All reactions contained 20 μM high purity S -adenosyl methionine (SAM, CisBio, Bedford, MA) in COMT assay buffer (50 mM Tris, 5–10 mM MgCl 2 , 2.5 mM DTT, pH 6.9). For MB-COMT, the catechol substrate was 7 μM norepinephrine (MilliporeSigma, St. Louis, MO) and for S-COMT the substrate was 10 μM 7,8-dihydroxy-4-methylcoumarin (MilliporeSigma, St. Louis, MO).…”

“… 8 In vivo microdialysis and fast-scan cyclic voltammetry provide information on the state of dopaminergic neurotransmission in whole animal systems, but they are time-consuming, labor-intensive, and expensive, which makes them impractical for the early stages of drug discovery. 3 , 9 , 10 Cell lines that synthesize, release, and metabolize DA can potentially fill the gap between in vivo measures and cell-free systems.…”

“…Cell-free in vitro assays are high-throughput and can provide valuable information on the effects of compounds on specific targets, but these assays provide no information on cell permeability, downstream effects of target engagement, or potential toxicity . In vivo microdialysis and fast-scan cyclic voltammetry provide information on the state of dopaminergic neurotransmission in whole animal systems, but they are time-consuming, labor-intensive, and expensive, which makes them impractical for the early stages of drug discovery. ,, Cell lines that synthesize, release, and metabolize DA can potentially fill the gap between in vivo measures and cell-free systems.…”

Discovery and characterization of naturally occurring potent inhibitors of catechol-O-methyltransferase from herbal medicines

“…7,8 Notably, different COMT inhibitors are widely used for the treatment of Parkinson's disease, and effectively improve the pharmacokinetic behavior of exogenously administered L-DOPA, extend the half-life, and increase bioavailability. [9][10][11][12] Due to the important role of COMT in the pathophysiology of different human diseases, they have undertaken extensive efforts to identify COMT inhibitors and several types of COMT inhibitors with different structures were developed. 13,14 Firstgeneration COMT inhibitors are characterized by a catechol skeleton, such as pyrogallol and caffeic acid.…”

Development of a PC12 cell-based assay forin vitroscreening of catechol-O-methyltransferase inhibitors

“…8 In vivo microdialysis and fast-scan cyclic voltammetry provide information on the state of dopaminergic neurotransmission in whole animal systems, but are time-consuming, labor-intensive, and expensive, which makes them impractical for the early stages of drug discovery. 3, 9, 10 Cell lines that synthesize, release, and metabolize DA can potentially fill the gap between in vivo measures and cell-free systems.…”