title: Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction.
abstract: A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA. fic@rti.org
authors.forename: F Ivy
authors.initials: FI
authors.lastname: Carroll
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: Philip
authors.initials: P
authors.lastname: Abraham
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Mills
authors.forename: J Ashley
authors.initials: JA
authors.lastname: Holleman
authors.forename: Scott A
authors.initials: SA
authors.lastname: Wolckenhauer
authors.forename: Ann M
authors.initials: AM
authors.lastname: Decker
authors.forename: Antonio
authors.initials: A
authors.lastname: Landavazo
authors.forename: K Timothy
authors.initials: KT
authors.lastname: McElroy
authors.forename: Hernán A
authors.initials: HA
authors.lastname: Navarro
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gatch
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forster
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016642:Bupropion / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004193:Discrimination Learning / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018759:Adrenergic Uptake Inhibitors; D016642:Bupropion; D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors