DAT Conformation Does Not Predict the Ability of Atypical Dopamine Uptake Inhibitors to Substitute for Cocaine

Hiranita, Takato

doi:10.4172/2329-6488.1000e132

Cited by 1 publication

(3 citation statements)

References 13 publications

(21 reference statements)

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“…In contrast, Cys accessibility results and molecular dynamics simulations suggested that aryltropane analogs can bind DAT and stabilize its outward-facing conformations like cocaine, yet producing effects that differ from those of cocaine . In addition, some diphenylmethoxy derivatives also seem to prefer an outward-open DAT conformation . In this context, the only experimental evidence is the probable involvement of Trp84 in vanoxerine binding stabilization.…”

Section: Resultsmentioning

confidence: 94%

“… a Reference . b Reference . c Reference . d Reference . e Reference . f Reference . g Reference . h Reference . i Reference . j Reference . k Binding affinity for human transporters. l Binding affinity for rat transporter. m For each transporter, the experimental and predicted p K i values are reported. …”

Section: Resultsmentioning

confidence: 99%

“…38 In addition, some diphenylmethoxy derivatives also seem to prefer an outward-open DAT conformation. 39 In this context, the only experimental evidence is the probable involvement of Trp84 in vanoxerine binding stabilization. Our docking results show a binding pose filling the whole cavity and the propylphenyl chain of vanoxerine which protrudes toward the extracellular side.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Focus on Human Monoamine Transporter Selectivity. New Human DAT and NET Models, Experimental Validation, and SERT Affinity Exploration

Ortore

Orlandini

Betti

et al. 2020

ACS Chem. Neurosci.

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The most commonly used antidepressant drugs are the serotonin transporter inhibitors. Their effects depend strongly on the selectivity for a single monoamine transporter compared to other amine transporters or receptors, and the selectivity is roughly influenced by the spatial protein structure. Here, we provide a computational study on three human monoamine transporters, i.e., DAT, NET, and SERT. Starting from the construction of hDAT and hNET models, whose threedimensional structure is unknown, and the prediction of the binding pose for 19 known inhibitors, 3D-QSAR models of three human transporters were built. The training set variability, which was high in structure and activity profile, was validated using a set of in-house compounds. Results concern more than one aspect. First of all, hDAT and hNET three-dimensional structures were built, validated, and compared to the hSERT one; second, the computational study highlighted the differences in binding site arrangement statistically correlated to inhibitor selectivity; third, the profiling of new inhibitors pointed out a conservation of the inhibitory activity trend between rabbit and human SERT with a difference of about 1 order of magnitude; fourth, binding and functional studies confirmed 4-(benzyloxy)-4-phenylpiperidine 20a−d and 21a−d as potent SERT inhibitors. In particular, one of the compounds (compound 20b) revealed a higher affinity for SERT than paroxetine in human platelets.

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Section: Resultsmentioning

confidence: 94%