Abuse of methamphetamine (MA) is a major health problem. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and has a tremendous societal impact. The National Institute on Drug Abuse has expressed considerable interest in the discovery of medications to address this problem. However, currently no medications are available for treatment of MA addiction. MA is a substrate for the Vesicular Monoamine Transporter-2 (VMAT2) located on intracellular storage vesicles in monoaminergic nerve terminals. The goal of this Phase 1 project is to design a potent and selective radioligand that reversibly labels the VMAT2 at a binding site that is coupled to functional activity of the VMAT2. A reversible [3H]ligand linked to functional activity f the VMAT2 will accelerate research toward discovery of medications for MA abuse. The unique ligands proposed here are designed to inhibit VMAT2 uptake by inhibition of the little explored [3H]reserpine binding site on VMAT2. A lead compound in the novel class of arylpiperidinylquinazolines (APQ) has already been demonstrated in our laboratories to bind reversibly at the [3H]reserpine binding site on the VMAT2. Optimization of this compound will now be achieved by sequential molecular modification with respect to binding potency at the VMAT2 and antagonist potency, as measured by inhibition of serotonin and dopamine uptake by the VMAT2. Further molecular modification will be conducted to optimize selectivity against competing binding sites. Topological changes will be introduced to explore the three-dimensional requirements of VMAT2 inhibition. Bioenantioselectivity of the VMAT2 binding site will be exploited by evaluation of enantiopure compounds. Compounds will be modified to optimize electronic, steric and lipophilic factors on functional and inhibitory potency at VMAT2. This project is expected to have a high impact on the search for MA pharmacotherapies as well as on the understanding of the molecular interaction of MA and potential medications that target the VMAT2.
Methamphetamine abuse, for which there are currently no medications available, has far reaching health consequences and a substantial societal impact. The goal of this project is to design radioligands as molecular tools to explore the interaction of methamphetamine with its biological target, the Vesicular Monoamine Transporter. These tools will accelerate the search for medications for methamphetamine addiction.
