Details

Autor(en) / Beteiligte

• Blasio, Angelo
• Wang, Jingyi
• Wang, Dan
• Varodayan, Florence P.
• Pomrenze, Matthew B.
• Miller, Jacklyn
• Lee, Anna M.
• McMahon, Thomas
• Gyawali, Sandeep
• Wang, Hua-Yu
• Roberto, Marisa
• McHardy, Stanton
• Pleiss, Michael A.
• Messing, Robert O.

Titel

Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice

Ist Teil von

• Biological psychiatry (1969), 2018-08, Vol.84 (3), p.193-201

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Despite the high cost and widespread prevalence of alcohol use disorders, treatment options are limited, underscoring the need for new, effective medications. Previous results using protein kinase C epsilon (PKCε) knockout mice, RNA interference against PKCε, and peptide inhibitors of PKCε predict that small-molecule inhibitors of PKCε should reduce alcohol consumption in humans. We designed a new class of PKCε inhibitors based on the Rho-associated protein kinase (ROCK) inhibitor Y-27632. In vitro kinase and binding assays were used to identify the most potent compounds. Their effects on ethanol-stimulated synaptic transmission; ethanol, sucrose, and quinine consumption; ethanol-induced loss of righting; and ethanol clearance were studied in mice. We identified two compounds that inhibited PKCε with Ki <20 nM, showed selectivity for PKCε over other kinases, crossed the blood-brain barrier, achieved effective concentrations in mouse brain, prevented ethanol-stimulated gamma-aminobutyric acid release in the central amygdala, and reduced ethanol consumption when administered intraperitoneally at 40 mg/kg in wild-type but not in Prkce−/− mice. One compound also reduced sucrose and saccharin consumption, while the other was selective for ethanol. Both transiently impaired locomotion through an off-target effect that did not interfere with their ability to reduce ethanol intake. One compound prolonged recovery from ethanol-induced loss of righting but this was also due to an off-target effect since it was present in Prkce−/− mice. Neither altered ethanol clearance. These results identify lead compounds for development of PKCε inhibitors that reduce alcohol consumption.