ABSTRACT
The synthesis of the enantiomers of bupropion, (rac)-2-tert-butylamino-3'-chloropropiophenone 1 (Wellbutrin) is described. The enantiomers were compared with the racemate in both the tetrabenazine-induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain.
Subject(s)
Biogenic Amines/metabolism , Bupropion/chemical synthesis , Bupropion/pharmacology , Animals , Bupropion/chemistry , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dopamine/metabolism , Hypothalamus/drug effects , Hypothalamus/metabolism , Indicators and Reagents , Male , Mice , Mice, Inbred Strains , Norepinephrine/metabolism , Serotonin/metabolism , Stereoisomerism , Structure-Activity Relationship , Synaptosomes/drug effects , Synaptosomes/metabolism , Tetrabenazine/antagonists & inhibitors , Tetrabenazine/pharmacologySubject(s)
Thalassemia/blood , Adolescent , Adult , Child , Child, Preschool , Female , Hemoglobins/analysis , Hemoglobins/classification , Hepatomegaly/etiology , Humans , India , Male , Splenomegaly/etiology , Syndrome , Thalassemia/complicationsABSTRACT
The synthesis of a hapten useful in the radioimmunoassay of bupropion is described. Since bupropion has no functional group that can be easily derivatized, a hydroxypropyl group was incorporated into the molecule. Studies in cross-reactivity with possible metabolites required the synthesis of the 4'-hydroxy analogue of bupropion. This synthesis is also described.
Subject(s)
Propiophenones/analysis , Bupropion , Cross Reactions , Haptens/analysis , RadioimmunoassayABSTRACT
The chemical structure and synthesis of bupropion are described and compared with typical polycyclic antidepressants to point up the novelty and simplicity of this drug. The features of bupropion's substructure are discussed to help in understanding the observed pharmacological differences among bupropion, tricyclic antidepressants, and psychostimulants.
Subject(s)
Antidepressive Agents , Propiophenones , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Bupropion , Chemical Phenomena , Chemistry , Mice , Propiophenones/chemical synthesis , Propiophenones/pharmacology , Structure-Activity RelationshipABSTRACT
A radioimmunoassay (RIA) procedure for the quantification of bupropion (dl-2-tert-butylamino-3'-chloropropiophenone) in biological fluids is described. Immunization of rabbits with conjugates of bovine serum albumin and p-succinoyl propylbupropion or p-carbomethoxybupropion resulted in the production of antisera which are capable of detecting less than 1 ng ml-1 (100 pg actual mass) of bupropion in the RIA, utilizing [6-3H] bupropion as radioligand. The antisera used in these studies have low cross-reaction (approximately 0.1% or less) with known side chain metabolites of bupropion, but exhibit significant cross-reaction with p-hydroxybupropion (30.3%). Excellent agreement was obtained between RIA and high-pressure liquid chromatography determinations of bupropion concentrations in human plasma samples, but plasma or serum from bupropion-treated dogs, rats and mice required extraction from basic medium to remove some interference before RIA. The assay was applied to a study of bupropion disposition in two beagles of each sex after i.v. and p.o. administrations of bupropion hydrochloride (100 mg). The pharmacokinetic profile in dogs was best described by an open two-compartment model after either route of drug administration. Peak plasma bupropion levels after oral dosing were highly variable, ranging from 12.9 to 63.5 ng ml-1 at 26 to 32 min after drug administration. The mean terminal phase half-life of bupropion was calculated to be 1.73 hr after either route and the absolute oral bioavailability of the drug varied from 2.0 to 6.5%.
Subject(s)
Antidepressive Agents/metabolism , Propiophenones/metabolism , Animals , Antibody Specificity , Antidepressive Agents/blood , Bupropion , Chromatography, High Pressure Liquid , Dogs , Female , Humans , Kinetics , Male , Mice , Propiophenones/blood , Rabbits , Radioimmunoassay/methods , Rats , Species SpecificityABSTRACT
A selected group of alkoxy- and halogen-substituted 5-benzylidino- and 5-benzylhydantoins was prepared and screened for anticonvulsant activity as measured by the ability of the compound to prevent maximal electroshock and metrazol-induced threshold clonic seizures in rats. The structure-activity studies revealed 5-[3-(trifluoromethyl)benzyl]hydantoin (14) to be the most potent member of the series.
