title: Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release.
abstract: Bupropion (1), an α-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 α-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 α-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 α-aminophenone- (i.e., cathinone-) related agents acting as transporter inhibitors versus those acting as releasers.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298 United States.
authors.forename: Abdelrahman R
authors.initials: AR
authors.lastname: Shalabi
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: Walther
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298 United States.
authors.forename: Richard A
authors.identifier: 0000-0002-3600-9045
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects; D016642:Bupropion / Q000737:chemistry / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000470:Alkaloids; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018377:Neurotransmitter Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016642:Bupropion; C023665:cathinone
keywords: Dopamine transporter; cathinone analogues; drug abuse; norepinephrine transporter; serotonin transporter; synthetic cathinones