PROJECT SUMMARY Our application is in response to RFA-AA-20-007 [Medications Development for the Treatment of Alcohol Use Disorder (AUD)]. Initial evidence supporting a neuroimmune hypothesis for excessive alcohol consumption led us to test tetracyclines in reward- and dependence-models. Having shown reductions in drinking and acute withdrawal, we used structure-functional data to design new chemically modified minocycline (CMM) compounds for loss of antibiotic properties, but retention of known innate immune action. In collaboration with the NIAAA Division of Medications Development, we have created and tested 16 CMM analogs for potential treatment of AUD. Several have shown both a loss of antimicrobial action and improvement over minocycline to reduce drinking in animal models of high alcohol consumption. Following oral administration tests, we have now identified a lead (best choice) and a backup compound and are in the process of completing preclinical pharmacology and toxicology screens. Nearly 15 million people in the US and ~100 million worldwide suffer from AUD. Over 5% of all medical morbidities share an ethanol-related risk. Although there are three FDA approved drugs to treat AUD, and several others are used off-label, medications have shown only modest success (in ~20% of patients treated). As a consequence, there is an urgent need for new pharmacotherapeutics across the DSM-V AUD spectrum. In fact, improved drugs that reduce high alcohol consumption in either reward- or relief-seeking patients would be most desirable. Currently, gabapentin is used off label as such; it reduces alcohol consumption and dependence-related symptoms, but its modest effectiveness and significant side- effects leave opportunity for considerable improvement. As required by the FDA, preliminary data for our CMMs show a significant reduction of alcohol consumption in two mammalian species. We have patents covering over 100 tetracycline modifications for use in neuroinflammatory diseases, including AUD. Texas Tech University System holds the patent rights. They have been licensed to South Plains Biotechnology, Inc., AUD subdivision, LLC, which is owned, in part, by researchers associated with this project. As a consequence, the success of the below aims represent a positive step toward potential commercialization. We will complete four aims addressing: Aim 1: Development of manufacturing standards; Aim 2: Completion of pre-clinical IND enabling studies; Aim 3: Phase I clinical trial; single-ascending dose; Aim 4: Phase I clinical trial; multiple-ascending dose. Future Phase II plans include testing in reward- and relief-seeking AUD patients, first in a small trial with our Clinical Research Institute and then in cooperation with the NIAAA Clinical Investigations Group. Impact: The development of a drug without addiction potential that successfully treats reward- and relief-driven AUD is critically needed. Our NIAAA collaboration, TTUHSC team, scientific adviser...