Development of Tetracycline Analogs for Alcohol Use Disorder Treatment

Project Summary Abstract Statement of the problemOnly three pharmacotherapeutic treatments for Alcohol Use DisorderAUDare FDA approved and none are widely usedandltof AUD patientsor show a strong effect to reduce riskyor dependence based drinking in the long termandltsee sustained decreased drinking outcomesUnfortunatelyapproximatelyof the population suffers from AUD and overof all medical morbidities share risky ethanol consumption as an underlying issueAs a consequenceintoxicationin generalandalcohol addictionsevere AUDin particularare important clinical problemsGiven the limited pharmacotherapeutic choicethere is a compelling need for continued development of new treatments across the AUD spectrummild to severe DSMV classificationOur published and preliminary data indicated an efficacy of tetracycline analogs with CH to reduce several important traits related to AUDincluding decreases in binge drinkingchronicdependencerelatedconsumptionphysical withdrawal symptoms and ethanol induced pain sensitizationHowevera healthy microbiota has recently garnered much attentionThereforewe designed seven new minocycline analogs that have no antimicrobial action and should not negatively affect GI functionPreliminary data demonstrated positive results in high consumption murine and porcine AUD modelsIn this STTR applicationfor Phase Iwe propose preclinical studies to determine the potential to treat AUD for the seven chemically modified tetracycline analogsCMTsPhase I will evaluate the hypothesis that our newly designed CMTs without antimicrobial properties will be effective in the reduction of binge and dependence drinkingconsistent with translation for use in human treatment of mild to severe AUDalcohol abuseandalcoholismWe will identify a lead compound using the following aimsAimCMTs will be verified for loss of antibiotic activity and chemical structure using CFU assays and NMR and MS respectivelyAimDevelopment of lead compounds will be completed using drug screens for AUD traits in CBLJ miceAnalogs will be tested for efficacy to lowerbingeacuteanddependencechronicconsumption in AUD modelswhich importantly reach pharmacologically relevant blood alcohol levelsAimA dose response relationship will be tested for two lead compounds using AimtestsFuture Phase II plans include the testing of lead compounds in our novel swine model and pharmacokinetic studies to understand timing for best therapeutic value as well as potential for development of tolerancefollowed by toxicology screensImpactThe development of a drug without addiction potential that targets several aspects of AUD symptomsdrinkingwithdrawalassociated painhas critical advantages over current therapies Public Health Relevance StatementProject NarrativeAlcohol Use DisorderAUDis a complex spectrum disorder that presents unmet clinical treatment challengesAccumulating evidence indicates that the action of ethanol on the innate immune system leads to chronification of risky drinkingpotential physical dependenceand often dangerous withdrawal symptomsThe proposed preclinical Phaseproject addresses testing tetracycline analogs without antibiotic properties for the development of lead compounds to treat AUDincluding binge and chronic ethanol consumption