(2R,3R)-Hydroxybupropion

(2R,3R)-Hydroxybupropion
Clinical data
Other names	(R,R)-Hydroxybupropion
Pharmacokinetic data
Metabolism	Glucuronidation
Metabolites	Hydroxybupropion glucuronide
Elimination half-life	19–26 hours
Identifiers
	IUPAC name (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol;
CAS Number	192374-15-5;
PubChem CID	9943908;
ChemSpider	8119520;
ChEMBL	ChEMBL1172929;
CompTox Dashboard (EPA)	DTXSID40433176 ;
Chemical and physical data
Formula	C13H18ClNO2
Molar mass	255.74 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H]1[C@](OCC(N1)(C)C)(C2=CC(=CC=C2)Cl)O;
	InChI InChI=1S/C13H18ClNO2/c1-9-13(16,17-8-12(2,3)15-9)10-5-4-6-11(14)7-10/h4-7,9,15-16H,8H2,1-3H3/t9-,13+/m1/s1; Key:RCOBKSKAZMVBHT-RNCFNFMXSA-N;

(2R,3R)-Hydroxybupropion, or simply (R,R)-hydroxybupropion, is the major metabolite of the antidepressant, smoking cessation, and appetite suppressant medication bupropion.^[3]^[4]^[1]^[5] It is the (2R,3R)-enantiomer of hydroxybupropion, which in humans occurs as a mixture of (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion (radafaxine).^[4]^[5] Hydroxybupropion is formed from bupropion mainly by the cytochrome P450 enzyme CYP2B6.^[4]^[1]^[2] Levels of (2R,3R)-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy.^[4]^[2]^[5]

^ ^a ^b ^c ^d ^e Costa R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metab Rev. 51 (3): 293–313. doi:10.1080/03602532.2019.1620763. PMID 31124380.
^ ^a ^b ^c ^d ^e Dash RP, Rais R, Srinivas NR (September 2018). "Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion". Xenobiotica. 48 (9): 945–957. doi:10.1080/00498254.2017.1376765. PMID 28876959.
^ Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006). "Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent". CNS Drug Rev. 12 (3–4): 178–207. doi:10.1111/j.1527-3458.2006.00178.x. PMC 6506196. PMID 17227286.
^ ^a ^b ^c ^d Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv Pharmacol. Vol. 69. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 978-0-12-420118-7. PMID 24484978. The hydroxylation of bupropion to form hydroxybupropion occurs by cytochrome P450 2B6 (CYP2B6) oxidation (Faucette et al., 2000; Faucette, Hawke, Shord, Lecluyse, & Lindley, 2001; Hesse et al., 2000), and the subsequent cyclization results in the creation of a second chiral center with the potential for the generation of two diastereomers (Suckow, Zhang, & Cooper, 1997). Interestingly, only the trans-diastereomers, (2S,3S)- and (2R,3R)-hydroxybupropion (2a and 2b, respectively), have been found in plasma in humans and when synthesized de novo (Fang et al., 2000), indicating that they are the thermodynamically more stable isomers. Steric hindrance greatly reduces cyclization to the cis-diastereomers, (2R,3S)- and (2S,3R)-hydroxybupropion (Suckow et al., 1997). The chirality of the second stereocenters is determined by the configuration of the existing stereocenter alpha to the ketone derived from either (S)- or (R)- bupropion.
^ ^a ^b ^c Cite error: The named reference KharaschNeinerKraus2020 was invoked but never defined (see the help page).

[CostaOliveiraDinis-Oliveira2019-1] Costa R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metab Rev. 51 (3): 293–313. doi:10.1080/03602532.2019.1620763. PMID 31124380.

[DashRaisSrinivas2018-2] Dash RP, Rais R, Srinivas NR (September 2018). "Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion". Xenobiotica. 48 (9): 945–957. doi:10.1080/00498254.2017.1376765. PMID 28876959.

[DwoskinRauhutKing-Pospisil2006-3] Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006). "Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent". CNS Drug Rev. 12 (3–4): 178–207. doi:10.1111/j.1527-3458.2006.00178.x. PMC 6506196. PMID 17227286.

[CarrollBloughMascarella2014-4] Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv Pharmacol. Vol. 69. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 978-0-12-420118-7. PMID 24484978. The hydroxylation of bupropion to form hydroxybupropion occurs by cytochrome P450 2B6 (CYP2B6) oxidation (Faucette et al., 2000; Faucette, Hawke, Shord, Lecluyse, & Lindley, 2001; Hesse et al., 2000), and the subsequent cyclization results in the creation of a second chiral center with the potential for the generation of two diastereomers (Suckow, Zhang, & Cooper, 1997). Interestingly, only the trans-diastereomers, (2S,3S)- and (2R,3R)-hydroxybupropion (2a and 2b, respectively), have been found in plasma in humans and when synthesized de novo (Fang et al., 2000), indicating that they are the thermodynamically more stable isomers. Steric hindrance greatly reduces cyclization to the cis-diastereomers, (2R,3S)- and (2S,3R)-hydroxybupropion (Suckow et al., 1997). The chirality of the second stereocenters is determined by the configuration of the existing stereocenter alpha to the ketone derived from either (S)- or (R)- bupropion.

[KharaschNeinerKraus2020-5] Cite error: The named reference KharaschNeinerKraus2020 was invoked but never defined (see the help page).

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