Threohydrobupropion

Threohydrobupropion (developmental code names BW 494, BW A494U) is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin).^[1][2] Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities.^[1]

Threohydrobupropion

(1S,2S)-Threohydrobupropion
Clinical data
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]
Elimination half-life	37 hours[1][2]
Identifiers
IUPAC name rel-(1R*,2R*)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-ol
CAS Number	92264-82-9 Y (racemate) 153365-82-3 (R,R) 102141-12-8 (S,S)
PubChem CID	9943534
ChemSpider	8010403
UNII	988C8SFV4F
ChEMBL	ChEMBL1304
CompTox Dashboard (EPA)	DTXSID70431488
ECHA InfoCard	100.216.731
Chemical and physical data
Formula	C13H20ClNO
Molar mass	241.76 g·mol−1
3D model (JSmol)	Interactive image
SMILES [C@H]([C@@H](NC(C)(C)C)C)(O)C1=CC(Cl)=CC=C1
InChI InChI=1/C13H20ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,12,15-16H,1-4H3/t9-,12+/s2 Key:NDPTTXIBLSWNSF-JVMLCUHDNA-N

Chemistry

Threohydrobupropion exists as a racemic mixture of two stereoisomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion.^[3][1] Other metabolites of bupropion include hydroxybupropion and erythrohydrobupropion.^[1][2]

Pharmacology

Information on the pharmacological actions of threohydrobupropion is scarce.^[1] In any case, it is about 20% as pharmacologically potent as bupropion and in the range of 20 to 50% as potent as bupropion in mouse models of depression.^[1][2] Moreover, threohydrobupropion has been reported to weakly inhibit the reuptake of norepinephrine, dopamine, and serotonin with rat IC₅₀Tooltip half-maximal inhibitory concentration or K_i 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] Besides monoamine reuptake inhibition, threohydrobupropion has also been reported to inhibit α₃β₄ 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]

The plasma protein binding of threohydrobupropion is 42%.^[1] Threohydrobupropion is formed from bupropion via reduction of the ketone group by 11β-hydroxysteroid dehydrogenase-1 and aldo-keto reductases.^[1] It can also be formed from bupropion by carbonyl reductases.^[1][2] The compound is metabolized by the cytochrome P450 enzymes CYP2B6 and CYP2C19 into threo-4'-hydroxy-hydrobupropion and by various glucuronosyltransferase enzymes into glucuronide conjugates.^[1] Its elimination 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 produces seizures at sufficiently high doses similarly to bupropion and other metabolites.^[1] Threohydrobupropion is a CYP2D6 inhibitor and accounts for about 21% of CYP2D6 inhibition during bupropion therapy, with hydroxybupropion accounting for 65% and erythrohydrobupropion accounting for 9%.^[1]