Development of Novel Therapies for Methamphetamine Abuse

The abuse of methamphetamine (METH) has escalated in recent years and effective treatments to curtail its use are not yet available. Our preliminary results demonstrate that a-lobeline (LOB), a weakly basic lipophilic alkaloid, binds to the high affinity nicotinic receptor binding site (a4P2 subtype) and acts as an antagonist at the nicotinic receptor subtype which evokes dopamine (DA) release (purportedly, the a3P2 subtype). LOB also inhibits the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2), but does not inhibit monoamine oxidase (MAO). Moreover, LOB inhibits amphetamine (AMPT)-evoked DA release and METH self-administration in rats. Our preliminary results suggest that VMAT2 may be an important new therapeutic target for the treatment of METH abuse. With this in mind, we have begun synthesizing a series of LOB analogs to target VMAT2. The long-term goal of this proposal is to develop our lead LOB analog, 2R,6S-N-methyl-2,6