Administrative Supplement: Development of Novel Therapeutics for Methamphetamine Abuse

Methamphetamine (METH) use disorder is linked to dire health and societal consequences. Effective treatments for METH addiction are not available. METH interacts with the vesicular monoamine transporter-2 (VMAT2), promoting dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA, resulting in abuse liability. This project focuses on VMAT2 as a novel therapeutic target, with the overall goal of obtaining a treatment for METH use disorder. Phase 1b studies with lobeline, the initial lead, were completed; however, bitter taste and multiple daily doses were expected to reduce compliance. Thus, lobeline was modified to obtain GZ-793A, which had the desired pharmacological properties, but had hERG toxicity. We next, identified novel small molecules, GZ-11608 and JPC-077, with greatly reduced hERG interaction, and potent and selective inhibition of VMAT2 function and METH-evoked DA release. Moreover, these leads specifically decrease METH self-administration in rats at doses that do not alter food reinforcement; no tolerance develops upon repeated dosing. Decreases in METH seeking in both METH and cue-induced reinstatement assays suggest efficacy against relapse. Acute pretreatment protects against METH-induced striatal DA neurotoxicity. Despite this favorable pharmacologic profile, these analogs have low oral bioavailability. Therefore, the focus of this application is to discover/develop optimized GZ-11608 and JPC-077 analogs with increased oral bioavailability. First, we will substitute deuterium for hydrogen at sites of metabolic liability. If deuterium substitution is not successful, we will synthesize, using rational design, a focused library, based on each lead. A chemoinformatic model has been built using our library of > 500 VMAT2 targeted compounds to predict optimized analogs with decreased metabolic liability and desirable drugable properties. Each analog, from deuterium substitution and medchem approaches, will be synthesized and evaluated for inhibition of VMAT2 and selectivity, as well as metabolism in rat and human liver microsomes. We will then assess the pharmacokinetics (PK) to determine oral bioavailability, plasma and brain concentrations and estimate PK parameters following IV, PO and SC dosing. Metabolites exceeding 10% will be synthesized and evaluated for toxicity and potential use as active pharmaceutical ingredient (API). We will then determine the dose-related inhibition of METH self-administration and reinstatement. Development of tolerance following repeated administration will be determined. We will conduct abbreviated toxicokinetics in rats and assess the potential for off-target interactions and CYP450 inhibition/induction. We will relate the pharmacokinetics of optimized analogs to pharmacodynamic effects, and determine the maximum tolerated dose, therapeutic index and behavioral specificity. Completion of this optimization program will allow for immediate transition of our leads into IND-enabling studies. Successful completion of the project should have a tremendously beneficial health and socioeconomic impact on society, since currently there are no available treatments for METH use disorder.