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

ABSTRACT: BACKGROUND: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 (PKC?) knockout mice, RNA interference against PKC?, and peptide inhibitors of PKC? predict that small-molecule inhibitors of PKC? should reduce alcohol consumption in humans. METHODS:We designed a new class of PKC? 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. RESULTS:We identified two compounds that inhibited PKC? with Ki <20 nM, showed selectivity for PKC? 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. CONCLUSIONS:These results identify lead compounds for development of PKC? inhibitors that reduce alcohol consumption.

SUBMITTER: Blasio A 

PROVIDER: S-EPMC5984071 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature