Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 8/15/00 → 6/30/16 |
Funding
- National Institute on Drug Abuse: $699,330.00
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