Small molecule modulators of RXFP3 for alcohol use disorder

PROJECT SUMMARY The goal of this project is to develop RXFP3 negative allosteric modulators (NAMs) to treat alcohol use disorder (AUD). AUD is a heterogeneous, chronic, relapsing disorder. Current medications for AUD, such as disulfiram, acamprosate and naltrexone, suffer from limited efficacy and intolerable side effects. Therefore, there is an urgent need for novel pharmacological interventions that are more effective for treating AUD. Recent preclinical studies have demonstrated the premise of relaxin-3/RXFP3 antagonism as a novel target for drug development to treat alcohol addiction and relapse. Our team has developed the first-in-class nonpeptide, brain-penetrant RXFP3 NAMs, represented by RLX-33, which can block relaxin-3 agonist activity in vitro and in vivo. These RXFP3 NAMs are highly selective against RXFP1 and RXFP4, two receptor subtypes in the relaxin/insulin superfamily. Our studies demonstrated that RLX-33 and the second-generation lead RLX-79 significantly reduced alcohol self-administration without having effects on general locomotor activity, sucrose self-administration, and anxiety-like behaviors. In this application, we propose to further optimize our lead-like compounds to improve potency and ADME/PK properties (Aims 1 and 2) and evaluate their effects in animal models of alcohol reinforcement and relapse-like behavior, as well as their potential affective-related side effects (Aim 3). Overall, completion of this project will identify novel RXFP3 NAMs as potential therapeutic agents for the treatment of AUD.