(2R,3R)-Hydroxybupropion

Major metabolite of the antidepressant bupropion (2R,3R)-Hydroxybupropion (2R,3R)-Hydroxybupropion.svg skin-invert-image Glucuronidation Hydroxybupropion glucuronide 19–26hours 192374-15-5 9943908 8119520 1172929 (R,R)-Hydroxybupropion (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol 13 18 1 1 2 C[C@@H]1[C@](OCC(N1)(C)C)(C2=CC(=CC=C2)Cl)O 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 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. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent CNS Drug Rev 12 3–4 178–207 2006 17227286 6506196 10.1111/j.1527-3458.2006.00178.x Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse Bupropion and bupropion analogs as treatments for CNS disorders Adv Pharmacol 69 177–216 2014 24484978 10.1016/B978-0-12-420118-7.00005-6 978-0-12-420118-7 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. Costa R, Oliveira NG, Dinis-Oliveira RJ Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects Drug Metab Rev 51 3 293–313 August 2019 31124380 10.1080/03602532.2019.1620763 It is the (2R,3R)-enantiomer of hydroxybupropion, which in humans occurs as a mixture of (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion (radafaxine). Hydroxybupropion is formed from bupropion mainly by the cytochrome P450 enzyme CYP2B6. Dash RP, Rais R, Srinivas NR Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion Xenobiotica 48 9 945–957 September 2018 28876959 10.1080/00498254.2017.1376765 Levels of (2R,3R)-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy. Exposure with bupropion Bupropion is substantially converted into metabolites during first-pass metabolism with oral administration and levels of its metabolites are much higher than those of bupropion itself. Exposure to (2R,3R)-hydroxybupropion is 29-fold higher than to (R)-bupropion and exposure to (2S,3S)-hydroxybupropion is 3.7-fold higher than to (S)-bupropion. Other metabolites that circulate at higher concentrations than those of bupropion include threohydrobupropion and to a lesser extent erythrohydrobupropion. The metabolism of bupropion and its metabolites is stereoselective. Kharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults Clin Pharmacol Ther 108 5 1036–1048 November 2020 32386065 10.1002/cpt.1888 During bupropion therapy, exposure to (R)-bupropion is 2- to 6-fold higher than to (S)-bupropion and exposure to (2R,3R)-hydroxybupropion is 20- to 65-fold higher than to (2S,3S)-hydroxybupropion. Hence, (2R,3R)-hydroxybupropion is a major metabolite of bupropion and (2S,3S)-hydroxybupropion is a minor metabolite. In contrast to humans, only low levels of hydroxybupropion or (2R,3R)-hydroxybupropion occur with bupropion in rats. This highlights substantial species differences in the pharmacokinetics of bupropion between animals and humans. These differences in turn may account for differences in the pharmacodynamic effects of bupropion between species. Pharmacology Pharmacodynamics (2R,3R)-Hydroxybupropion is much less pharmacologically active as a monoamine reuptake inhibitor than bupropion or (2S,3S)-hydroxybupropion. Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors Mol Pharmacol 66 3 675–682 September 2004 15322260 10.1124/mol.104.001313 Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation J Med Chem 53 12 4731–4748 June 2010 20509659 2895766 10.1021/jm1003232 Carroll FI, Muresan AZ, Blough BE, Navarro HA, Mascarella SW, Eaton JB, Huang X, Damaj MI, Lukas RJ Synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues and their effects on monoamine uptake, nicotinic acetylcholine receptor function, and behavioral effects of nicotine J Med Chem 54 5 1441–1448 March 2011 21319801 3048909 10.1021/jm1014555 Conversely, its potency as a negative allosteric modulator of nicotinic acetylcholine receptors is variable but overall more similar to that of bupropion and (2S,3S)-hydroxybupropion. + Bupropion and hydroxybupropion functional activities (IC50 half-maximal inhibitory concentration) at human biological targetsLiu Tiqing Binding Database Home BindingDB 4 August 2024 https://www.bindingdb.org/rwd/bind/index.jsp 19 August 2024PDSP Database UNC https://pdsp.unc.edu/databases/pdsp.php zu 19 August 2024(R,R)-Hydroxy Bupropion - Biological Test Results PubChem https://pubchem.ncbi.nlm.nih.gov/compound/9943908#section=Biological-Test-Results 19 August 2024 Compound Monoamine reuptake inhibition nAChR Nicotinic acetylcholine receptor inhibition Ref DA Dopamine NE Norepinephrine 5-HT Serotonin (5-hydroxytryptamine) α3β4 α4β2 α4β4 α1β1 Bupropion 660–2,900 1,450–1,850 >10,000–47,000 1,800 12,000 12,000–14,000 7,900 Eshleman AJ, Carmolli M, Cumbay M, Martens CR, Neve KA, Janowsky A Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type J Pharmacol Exp Ther 289 2 877–885 May 1999 10215666 10.1016/S0022-3565(24)38214-X (2R,3R)-Hydroxybupropion >10,000 9,900 >10,000 6,500 31,000 41,000 7,600 (2S,3S)-Hydroxybupropion 630 241 >10,000 10,000–11,000 3,300 30,000 28,000 Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site. + Bupropion and hydroxybupropion inhibition (IC50 half-maximal inhibitory concentration, nM) of rat monoamine transporters Compound DAT Dopamine transporter NET Norepinephrine transporter Bupropion 550 ± 65 1900 ± 12 (2RS,3RS)-Hydroxybupropion >10000 1700 ± 830 (2S,3S)-Hydroxybupropion 790 ± 11 520 ± 35 (2R,3R)-Hydroxybupropion >10000 >10000 Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site. Additional studies have characterized the affinities (Ki) of bupropion and the hydroxybupropion enantiomers at the monoamine transporters as well as affinities and potencies (IC50) using non-human proteins. Nelson DL, Gehlert DR Central nervous system biogenic amine targets for control of appetite and energy expenditure Endocrine 29 1 49–60 February 2006 16622292 10.1385/endo:29:1:49 In contrast to bupropion and (2S,3S)-hydroxybupropion, racemic hydroxybupropion, using rat proteins, has been found to act as a selective norepinephrine reuptake inhibitor (IC50 = 1,700nM) with no apparent inhibition of dopamine reuptake (IC50 > 10,000nM). Normally, activity with racemic mixtures is expected to be closer to that of the active enantiomer than to the inactive enantiomer. The reasons for the discrepancy in the case of racemic hydroxybupropion are unclear. In any case, it was suggested that (2R,3R)-hydroxybupropion might be acting as a negative allosteric modulator of the binding of (2S,3S)-hydroxybupropion to the dopamine transporter. Bupropion and (2S,3S)-hydroxybupropion are substantially more potent than (2R,3R)-hydroxybupropion in various rodent behavioral tests, such as the forced swim test (an assay of antidepressant-like activity). However, sufficient doses of bupropion, (2S,3S)-hydroxybupropion, and (2R,3R)-hydroxybupropion all produce full methamphetamine-like effects in monkeys (1mg/kg, 3mg/kg, and 10mg/kg, respectively). Reith ME, Gnegy ME Molecular Mechanisms of Amphetamines Handb Exp Pharmacol Handbook of Experimental Pharmacology 258 265–297 2020 31286212 10.1007/164_2019_251 978-3-030-33678-3 Banks ML, Smith DA, Blough BE Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys Behav Pharmacol 27 2-3 Spec Issue 196–203 April 2016 26886209 4779668 10.1097/FBP.0000000000000224 Bupropion produces nicotine-like effects in rodents and (2S,3S)-hydroxybupropion partially substitutes for nicotine. In contrast, (2R,3R)-hydroxybupropion does not substitute for nicotine and dose-dependently antagonizes the effects of nicotine by up to 50%. (2R,3R)-Hydroxybupropion is a strong CYP2D6 inhibitor similarly to bupropion. (2R,3R)-Hydroxybupropion alone has been estimated to account for approximately 65% of the total in vivo CYP2D6 inhibition of bupropion, whereas threohydrobupropion accounted for 21% and erythrohydrobupropion accounted for 9% (with 5% remaining or unaccounted for). Pharmacokinetics Hydroxybupropion, including both (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion, is mainly formed from bupropion by the cytochrome P450 enzyme CYP2B6. However, CYP2C19, CYP3A4, CYP1A2, and CYP2E1 appear to play a minor role. CYP2B6 is highly polymorphic and is subject to high interindividual variability of approximately 100-fold. This may result in large interindividual differences in the metabolism of bupropion into hydroxybupropion and the effects of bupropion. However, clearance of bupropion is not affected in different CYP2B6 metabolizer phenotypes. This suggests that other enzymes compensate in the metabolism of bupropion in the context of reduced CYP2B6 function. The moderate CYP2B6 inducer rifampicin increased the clearance of (2R,3R)-hydroxybupropion and decreased its exposure and half-life by approximately 50%. The elimination half-life of (2R,3R)-hydroxybupropion is 19 to 26hours. Chemistry Hydroxybupropion has two chiral centers. Niemegeers P, Dumont GJ, Patteet L, Neels H, Sabbe BG Bupropion for the treatment of seasonal affective disorder Expert Opin Drug Metab Toxicol 9 9 1229–1240 September 2013 23705752 10.1517/17425255.2013.804062 As hydroxybupropion has two chiral centers, there are four possible enantiomers. However, only (R,R)-hydroxybupropion and (S,S)-hydroxybupropion are found in human plasma [62]. Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants World J Biol Psychiatry 22 8 561–628 October 2021 33977870 10.1080/15622975.2021.1878427 Bupropion is chiral and CYP2B6 stereoselective metabolism is observed with (S)-bupropion being metabolised at more than three times the rate of (R)-bupropion (Coles and Kharasch 2008). Because hydroxybupropion has two chiral centres, four enantiomers should be observed: however, only (R,R)-hydroxybupropion and (S,S)- hydroxybupropion are found (Coles and Kharasch 2008). 11250/2981927 free As a result, there are four possible enantiomers of the compound. However, only (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion are formed in humans. (2R,3S)- and (2S,3R)-Hydroxybupropion do not occur in humans presumably due to steric hindrance precluding their formation. Batra S, Bhushan R Resolution of enantiomers of bupropion and its metabolites by liquid chromatography Biomed Chromatogr 30 5 670–682 May 2016 26230937 10.1002/bmc.3572 S,S)- and (R,R)-hydroxybupropion have been found in plasma in humans, presumably owing to steric hindrance precluding formation of (R,S)- and (S,R)-hydroxybupropion. References Category:Antidepressants Category:Cathinones Category:3-Chlorophenyl compounds Category:CYP2D6 inhibitors Category:Enantiopure drugs Category:Human drug metabolites Category:Morpholines Category:Nicotinic antagonists Category:Norepinephrine–dopamine reuptake inhibitors Category:Smoking cessation Category:Stimulants Category:Tertiary alcohols