Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation




Pharmaceutical Sciences

First Advisor

Dr. Peter A. Crooks


Methamphetamine (METH) abuse is a serious problem in the United States and worldwide. The reward experienced by METH users is due to the increase in extracellular dopamine (DA) concentrations caused by an interaction between METH and the DA transporter (DAT) as well as the Vesicular Monoamine Transporter-2 (VMAT2). The reward felt by users of METH leads to further use of the drug and subsequent abuse. The current project examined the ability of three novel series of lobelane analogs to interact with a binding site on the Vesicular Monoamine Transporter-2 (VMAT2) in an attempt to inhibit the effects of METH. Lobelane is a defunctionalized analog of Lobeline, a natural product found in Lobelia inflata which has been shown to bind to VMAT2 and inhibit its function. Rational drug design methodology and organic synthesis was used to generate a library of three series of lobelane analogs. In total, 107 compounds were synthesized and examined. Compounds were assayed for affinity in a high-throughput [3H] dihydrotetrabenazine (DTBZ) radioligand binding screen as well as for function in a [3H] DA uptake assay. Several compounds were identified which possess affinity as well as selectivity for the DTBZ binding site on VMAT2 [JPC-077 (Ki=0.19 μM), JPC-094 (Ki=0.15 μM), JPC-096 (Ki=0.19 μM), and JPC-106 (Ki=0.19 μM)]. The same four compounds exhibited inhibition of [3H]DA uptake [JPC-077 (Ki=9.3 nM), JPC-094 (Ki=13 nM), JPC-096 (Ki=20 nM), and JPC-106 (Ki=83 nM)]. With the assay data generated from the library of compounds, several structure activity relationship (SAR) based ligand based pharmacophore models were developed to guide future ligand design.