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 (1S,2S)-Threohydrobupropion | |
| Clinical data | |
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| Other names | threo-Hydrobupropion; Threohydroxybupropion; BW 494; BW A494U;threo-3-Chloro-N-tert-butyl-β-hydroxy-α-methylphenethylamine;threo-3-Chloro-N-tert-butyl-β-hydroxyamphetamine |
| Pharmacokinetic data | |
| Protein binding | 42%[1] |
| Metabolism | Hydroxylation (CYP2B6,CYP2C19),glucuronidation (UGTs)[1] |
| Eliminationhalf-life | 37 hours[1][2] |
| Identifiers | |
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| PubChemCID | |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.216.731 |
| Chemical and physical data | |
| Formula | C13H20ClNO |
| Molar mass | 241.76 g·mol−1 |
| 3D model (JSmol) | |
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Threohydrobupropion (developmental code namesBW 494,BW A494U) is asubstituted amphetaminederivative—specifically aβ-hydroxyamphetamine—and a majoractive metabolite of theantidepressant drugbupropion (Wellbutrin).[1][2] Bupropion is anorepinephrine–dopamine reuptake inhibitor andnicotinic acetylcholine receptornegative allosteric modulator, with itsmetabolites contributing substantially to its activities.[1]
Threohydrobupropion exists as aracemic mixture of twostereoisomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion.[3][1] Other metabolites of bupropion includehydroxybupropion anderythrohydrobupropion.[1][2]
Information on thepharmacological actions of threohydrobupropion is scarce.[1] In any case, it is about 20% as pharmacologicallypotent as bupropion and in the range of 20 to 50% as potent as bupropion inmouse models of depression.[1][2] Moreover, threohydrobupropion has been reported to weaklyinhibit thereuptake ofnorepinephrine,dopamine, andserotonin with ratIC50Tooltip half-maximal inhibitory concentration or Ki values of 16 μM, 47 μM, and 67 μM, respectively.[4] These values can be compared to rat values with bupropion of 1,400 nM, 570 nM, and 19,000 nM, respectively.[4] Besidesmonoamine reuptake inhibition, threohydrobupropion has also been reported to inhibitα3β4 nicotinic acetylcholine receptors, with an IC50 value of 14 μM.[5] Threohydrobupropion circulates at higher concentrations than bupropion during bupropion therapy, similarly to hydroxybupropion but in contrast to erythrohydrobupropion—which circulates at similar concentrations as bupropion.[1][2]
Theplasma protein binding of threohydrobupropion is 42%.[1] Threohydrobupropion is formed from bupropion viareduction of theketone group by11β-hydroxysteroid dehydrogenase-1 andaldo-keto reductases.[1] It can also be formed from bupropion bycarbonyl reductases.[1][2] The compound ismetabolized by thecytochrome P450enzymesCYP2B6 andCYP2C19 into threo-4'-hydroxy-hydrobupropion and by variousglucuronosyltransferase enzymes intoglucuronideconjugates.[1] Itselimination half-life is approximately 37 hours.[1][2]
Dry mouth during bupropion therapy has been associated with threohydrobupropion concentrations.[1] Administration of threohydrobupropion in mice producesseizures at sufficiently high doses similarly to bupropion and other metabolites.[1] Threohydrobupropion is aCYP2D6inhibitor and accounts for about 21% of CYP2D6 inhibition during bupropion therapy, with hydroxybupropion accounting for 65% and erythrohydrobupropion accounting for 9%.[1]
