The aim of this research project is to develop peripherally restricted cannabinoid receptor 1 (CB1R) antagonists for alcoholic steatosis. Alcohol abuse has detrimental effects on many organs, most notably the liver causing steatosis (AS), steatohepatitis (ASH), and cirrhosis (AC). Previously considered benign, emerging data suggest that AS is a pathological condition by itself. Thus, medications that inhibit AS will be extremely useful for alcoholic liver disease (ALD). Antagonism of CB1R is a validated strategy for treating ALD. Unfortunately, the first approved CB1R antagonist rimonabant (SR141716), which was introduced in Europe as an anti-obesity pill, was withdrawn due to adverse effects in some users including depression and suicidal ideation. However, a growing body of evidence suggests that selective inhibition of peripheral CB1R, avoiding possible CNS related side effects, may be useful in the treatment of diseases where this CB1R sub-population is implicated. Thus, development of peripherally restricted CB1R antagonists that cannot permeate the blood-brain barrier (BBB) is an exciting strategy for treating ALD and associated disorders while limiting the CNS-related adverse events noted with non-tissue selective antagonists. Through our ongoing program, we have developed highly potent and selective CB1R antagonists based on a diphenyl purine scaffold that are amenable to further refinement. The goal of this proposal is to improve on the drug-like properties of these compounds to identify preclinical candidates for further development through four specific aims: (1) Analogs of a previously characterized CB1R antagonist will be modified for peripheral selectivity. We have already produced and reported compounds that are highly potent, selective, and have ~3-7% brain penetration. The goal will be to produce compounds that are more drug-like with <3% brain penetration. (2) Pharmacological characterization of these compounds will follow, including establishment of ADMET and pharmacokinetic properties to generate a priority list for in vivo efficacy studies. (3) Since non-tissue selective CB1R antagonists produce CNS-related adverse effects, compounds identified through aim 2 will be tested for blocking the effect of (-)--9-tetrahydrocannabinol (THC), which is a potent CB1R agonist in the tetrad assay of locomotor activity, antinociception, hypothermia, and catalepsy. These compounds will be further evaluated following chronic administration in an animal model of depression. (4) Efficacy studies will be performed in the Lieber-DeCarli model of AS. Efficacy related biomarkers will be evaluated. Mechanistic studies will be also performed to examine signaling pathways affected by CB1R antagonism. Candidate compounds with favorable properties will be identified for further development.