Amphetamine (AMPH) and its derivatives embody a remarkable breadth of pharmacology. These molecules exert their effects, both therapeutic and pathological, at the human monoamine transporters, which tune synaptic dynamics by evacuating monoamine neuromodulators from the synapse subsequent to neuronal impulses. These transporters are electrogenic, and the transporter-mediated current can be correlated to a surrogate measure of the change in membrane voltage: Ca++ currents from co-transfected L-type Ca++ channels. The present work makes use of this assay, with which it is possible to derive pharmacodynamic metrics from both substrates and inhibitors. This work presents data on a heretofore-unstudied class of amphetamine analogs: the enantiomers of N-Me 4-Me AMPH and N-Et 4-Me AMPH. Remarkably, while both enantiomers of the N-Me version of this compound function as substrates at hDAT, both enantiomers of the N-Et version are inhibitors. This switch does not occur at hNET, where all enantiomers of both N-Me and N-Et 4-Me AMPH function as substrates. Further, (S)-N-Et 4-Me AMPH is a substrate at dDAT. EC50 and IC50 values for all drugs at both transporters are presented. I present the results of super-resolution microscopic co-localization studies on the plasmalemmal spatial relation of the human dopamine transporter and voltage gated calcium channel, L-type 1.2 (CaV1.2). I discuss future aims toward a unified understanding of the mechanisms of monoamine transporter function, with an emphasis on what amphetamine can illuminate in this regard.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5501 |
| Date | 01 January 2016 |
| Creators | Harris, Alan C., Jr. |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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