Synthesis and biological evaluation of bupropion analogues as potential pharmacotherapies for cocaine addiction.
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.
Carroll
F Ivy
FI
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, USA. fic@rti.org
Blough
Bruce E
BE
Abraham
Philip
P
Mills
Andrew C
AC
Holleman
J Ashley
JA
Wolckenhauer
Scott A
SA
Decker
Ann M
AM
Landavazo
Antonio
A
McElroy
K Timothy
KT
Navarro
Hernán A
HA
Gatch
Michael B
MB
Forster
Michael J
MJ
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
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