SCOPE: Carry-Forward: Development of Novel Therapies for Methamphetamine Abuse

Methamphetamine (METH) abuse continues to escalate and effective treatments are not currently available. METH interacts with the vesicular monoamine transporter-2 (VMAT2), promoting both dopamine (DA) release into the cytosol and reversal of the DA transporter to increase extracellular DA concentrations, which is associated with its abuse liability. The overall objective of this project is to provide a clinical candidate for the treatment of METH abuse. We identified a novel small molecule (GZ-793A), which potently and selectively inhibits DA uptake by VMAT2, inhibits METH-evoked DA release from synaptic striatal vesicles and slices, and does not interact with nicotinic receptors or DA transporters. Off-target evaluation at a cadre of neurotransmitter-related, steroid and ion channel sites, second messenger, prostaglandin, growth factor and hormones, brain/gut peptides and enzymes revealed outstanding selectivity. Translation to whole animals models revealed that GZ-793A specifically decreases METH selfadministration without altering responding for sucrose, does not produce tolerance to the decrease in METH self-administration upon repeated administration, and decreases METH seeking in the cue-induced reinstatement. Acute GZ-793A pretreatment protects against the neurotoxic effects of METH (striatal DA depletion). Although the physicochemical properties of GZ-793A are favorable in terms of druggability, GZ-793A has only 2-3% oral bioavailability, likely due to the presence of the hydroxyl functionalities in the molecule which are likely sites for high first-pass metabolism. Preliminary data showed that GZ-793A is a substrate for CYP2D6 and CYP2C19 oxidative enzymes. Despite the low oral bioavailability of GZ-793A, preliminary data show that oral GZ-793A is effective at decreasing METH self-administration at high oral doses. Unfortunately, GZ-793A was found to have potential cardiotoxicity. We propose to overcome this problem through structural modification of GZ-793A and identification of at least one new lead that has high affinity for VMAT2, good selectivity for VMAT2, lack of predictive toxicology (specifically, lack of hERG interaction), lack of exacerbation of METH toxicity to DA neurons, and decrease METH-induced behavioral sensitization (rapid efficacy locomotor activity screen) following oral administration, and subsequently, decrease METH self-administration and reinstatement. Thus, we propose to optimize the analog series by structurally modifying GZ-793 to eliminate hERG interaction and the predicted cardiotoxicity. Such compounds would be high value preclinical candidates as treatments for METH abuse. Thus, we propose to expand our existing molecular library of analogs by performing the final steps of optimization of GZ-793A to identify a high value preclinical candidate as a potential therapeutics for METH abuse.