Bupropion and bupropion analogs as treatments for CNS disorders.
Bupropion, introduced as an antidepressant in the 1980s, is also effective as a smoking cessation aid and is beneficial in the treatment of methamphetamine addiction, cocaine dependence, addictive behaviors such as pathological gambling, and attention deficit hyperactivity disorder. (2S,3S)-hydroxybupropion is an active metabolite of bupropion produced in humans that contributes to antidepressant and smoking cessation efficacy and perhaps benefits in other CNS disorders. Mechanisms underlying its antidepressant and smoking abstinence remain elusive. However, it seems likely that efficacy is due to a combination of the effects of bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine (DA) and NE in reward centers of the brain and the noncompetitive antagonism of α4β2- and α3β4*-nAChRs. These combined effects of bupropion and its active metabolite may be responsible for its ability to decrease nicotine reward and withdrawal. Studies directed toward development of a bupropion analog for treatment of cocaine addiction led to compounds, typified by 2-(N-cyclopropylamino)-3'-chloropropiophenone (RTI-6037-39), thought to act as indirect DA agonists. In addition, (2S,3S)-hydroxybupropion analogs were developed, which had varying degrees of DA and NE uptake inhibition and antagonism of nAChRs. These compounds will be valuable tools for animal behavioral studies and as clinical candidates. Here, we review the (1) early studies leading to the development of bupropion, (2) bupropion metabolism and the identification of (2S,3R)-hydroxybupropion as an active metabolite, (3) mechanisms of bupropion and metabolite action, (4) effects in animal behavioral studies, (5) results of clinical studies, and (6) development of bupropion analogs as potential pharmacotherapies for treating nicotine and cocaine addiction.
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina, USA. Electronic address: fic@rti.org.
F Ivy
FI
Carroll
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina, USA.
Bruce E
BE
Blough
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina, USA.
S Wayne
SW
Mascarella
Discovery Sciences, Research Triangle Institute, Research Triangle Park, North Carolina, USA.
Hernán A
HA
Navarro
Division of Neurobiology, St. Joseph's Hospital and Medical Center, Barrow Neurological Institute, Phoenix, Arizona, USA.
Ronald J
RJ
Lukas
Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA.
M Imad
MI
Damaj
D000818:Animals; D016642:Bupropion / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D016896:Treatment Outcome
C580748:hydroxybupropion; D016642:Bupropion
Antidepressants; Bupropion analogs for nicotine addiction; Bupropion and bupropion analogs; Bupropion/nAChR binding; Dopamine and norepinephrine uptake inhibitors; Hydroxybupropion; Nicotinic receptor antagonists; Smoking cessation