Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release.
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Shalabi AR, Walther D, Baumann MH, Glennon RA
Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release.
ACS Chem Neurosci. 2017 Jun 21;8(6):1397-1403. doi: 10.1021/acschemneuro.7b00055. Epub 2017 Feb 27.
- PubMed ID
- 28220701 [ View in PubMed]
- Abstract
Bupropion (1), an alpha-aminophenone uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET), is a widely prescribed antidepressant and smoking cessation aid. Cathinone (2), a structurally simpler alpha-aminophenone, is a substrate-type releasing agent at the same transporters and a recognized drug of abuse. Our goal was to identify the structural features of alpha-aminophenones that govern the mechanistic transition from uptake inhibition to substrate-induced release. Deconstructed analogues of 1 were synthesized and compared for their ability to interact with DAT, NET, and the serotonin transporter (SERT) using in vitro assay methods. Bulky amine substituents resulted in compounds that function as DAT uptake inhibitors but not release agents, whereas smaller amine substituents result in relatively nonselective releasing agents at DAT and NET. Our findings add to empirical evidence supporting distinct molecular determinants for alpha-aminophenone- (i.e., cathinone-) related agents acting as transporter inhibitors versus those acting as releasers.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Bupropion Sodium-dependent dopamine transporter Protein Humans YesInhibitorDetails Bupropion Sodium-dependent noradrenaline transporter Protein Humans YesInhibitorDetails