Background New pharmacotherapies to treat Alcohol Use Disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol drinking in mice. To test the hypothesis that suppression of high ethanol consumption is a general property of tetracyclines, we screened several derivatives for anti-drinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. Methods Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% ethanol over a 4-day period. Mice were administered a tetracycline or its vehicle 20 h prior to drinking. Water and ethanol consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for ethanol content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced ethanol drinking, and doxycycline showed a strong effect-size trend towards reduced drinking. Subsequent studies with these three drugs revealed a dose-dependent decrease in ethanol consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on ethanol drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in ethanol consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition-coefficients (LogP) or distribution constants (LogD). Conclusions Due to its effectiveness in reducing high ethanol consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.

We report synthesis of potential initiators1a-Br,2a-Br, and3a-Br for the ATRP ofN-phenylitaconimide and MMA. We find (i) good agreement between experimentally determined and calculatedKATRPvalues (ii)3a-Br performs better than the commercially available initiator.

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