Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Jose M. Eltit


Monoamine transporters (MATs) are a unique group of neurotransmitter transporters that include the dopamine, serotonin, and norepinephrine transporters (DAT, SERT, and NET, respectively). MATs are a target for a number of licit and illicit compounds. The significance of this work lies in the fact that these transporters share affinity for certain ligands to varying degrees, but the structural features within the transporters that govern the observed selectivity for these ligands has not been completely determined. One such ligand is methylenedioxypyrovalerone (MDPV), which was frequently found in “bath salts” preparations that were available in convenience stores and were sold with “not for human consumption” labelling to circumvent drug laws. MDPV is highly selective for human DAT, and has a high abuse liability. SERT/DAT selectivity is one metric that correlates well with the abuse liability of psychostimulants, with higher affinity at human DAT (hDAT) and lower affinity at hSERT resulting in a higher associated abuse liability. In this work, we use a comparative 2D and 3D structural approach to compare hDAT, hSERT, and the Drosophila melanogaster dopamine transporter (dDAT) to determine residues that contribute to MDPV’s high affinity binding at hDAT. dDAT was used for its interesting hybrid pharmacology wherein hDAT selective blockers are weak at dDAT. We then made chimeric mutations in dDAT using site-directed mutagenesis and tested the mutants in a recently developed assay that exploits intracellular calcium as a reporter for MAT function. Four residues were identified, and in combination, these chimeric mutations almost fully recapitulate MDPV in dDAT.


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Available for download on Tuesday, August 06, 2024