title: Behavioral and biochemical investigations of bupropion metabolites.
abstract: The stimulus effects of bupropion metabolites were examined in a drug discrimination procedure using (-)nicotine- and (+)amphetamine-trained rats. (+)- and (-)threohydrobupropion partially substituted in each group. R,R-hydroxybupropion produced vehicle-appropriate responding in (-)nicotine animals but, when given in combination with the training dose of (-)nicotine, resulted in an attenuated effect. S,S-Hydroxybupropion partially (66%) substituted for (-)nicotine. In (+)amphetamine-trained animals, S,S-hydroxybupropion (ED50=4.4 mg/kg) generalized completely and was similar in potency to bupropion (ED50=5.4 mg/kg). Bupropion and its metabolites lacked affinity for nicotinic acetylcholinergic receptors, but all antagonized (-)nicotine-induced 86Rb+ efflux in cells expressing alpha3beta4 nicotinic cholinergic receptors. S,S-Hydroxybupropion possessed affinity at the dopamine transporter comparable to bupropion, and was also found to bind at the norepinephrine transporter. Although it is unlikely that any metabolite isomer is chiefly responsible for the stimulus actions of bupropion, some probably play a role in the complex actions of this agent.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 554A Smith Building 410 N. 12th Street, Box 980540, Richmond, VA 23298-0540, USA.
authors.forename: Mikhail L
authors.initials: ML
authors.lastname: Bondarev
authors.forename: Tatiana S
authors.initials: TS
authors.lastname: Bondareva
authors.forename: Richard
authors.initials: R
authors.lastname: Young
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D016642:Bupropion / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004193:Discrimination Learning / Q000187:drug effects*; D006801:Humans; D008297:Male; D009538:Nicotine / Q000008:administration & dosage; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012414:Rubidium Radioisotopes; D014162:Transfection
chemical_list: D018687:Antidepressive Agents, Second-Generation; D011978:Receptors, Nicotinic; D012414:Rubidium Radioisotopes; D016642:Bupropion; D009538:Nicotine; D000661:Amphetamine