Non-conserved residues dictate dopamine transporter selectivity for the potent synthetic cathinone and psychostimulant MDPV
| Autor: | Tyler W.E. Steele, Zachary Spires, Charles B. Jones, Jose M. Eltit, Richard A. Glennon, Malgorzata Dukat |
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| Rok vydání: | 2021 |
| Předmět: |
Pyrrolidines
medicine.drug_class Stereochemistry Article Cell Line Designer Drugs Cellular and Molecular Neuroscience Dopamine Uptake Inhibitors Dopamine medicine Animals Benzodioxoles Binding site Serotonin transporter Dopamine transporter Pharmacology Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins biology Chemistry Transporter Biological Transport Synthetic Cathinone Designer drug Molecular Docking Simulation Drosophila melanogaster Docking (molecular) biology.protein Calcium Channels Bath salts medicine.drug |
| Zdroj: | Neuropharmacology |
| ISSN: | 1873-7064 |
| Popis: | Clandestine chemists are currently exploiting the pyrrolidinophenone scaffold to develop new designer drugs that carry the risk of abuse and overdose. These drugs promote addiction through the rewarding effects of increased dopaminergic neurotransmission. 3,4-Methylenedioxypyrovalerone (MDPV) and its analogs are illicit psychostimulants of this class that are ~50-fold more potent than cocaine at inhibiting the human dopamine transporter (hDAT). In contrast, MDPV is a weak inhibitor at both the human serotonin transporter (hSERT) and, as it is shown here, the Drosophila melanogaster DAT (dDAT). We studied three conserved residues between hSERT and dDAT that are unique in hDAT (A117, F318, and P323 in dDAT), and one residue that is different in all three transporters (D121 in dDAT). hDAT residues were replaced in the dDAT sequence at these positions using site-directed mutagenesis and stable cell lines were generated expressing these mutant transporters. The potencies of MDPV and two of its analogs were determined using a Ca(2+)-mobilization assay. In this assay, voltage-gated Ca(2+) channels are expressed to sense the membrane electrical depolarization evoked when dopamine is transported through DAT. Each individual mutant slightly improved MDPV’s potency, but the combination of all four increased its potency ~100-fold (2 log units) in inhibiting dDAT activity. Molecular modeling and docking studies were conducted to explore the possible mode of interaction between MDPV and DAT in silico. Two of the studied residues (F318 and P323) are at the entrance of the S1 binding site, whereas the other two (A117 and D121) face the aryl moiety of MDPV when bound to this site. Therefore, these four non-conserved residues can influence MDPV selectivity not only by stabilizing binding, but also by controlling access to its binding site at DAT. |
| Databáze: | OpenAIRE |
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