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Radafaxine

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(Redirected from (S,S)-Hydroxybupropion)
Radafaxine
Clinical data
Other names(S,S)-Hydroxybupropion; (2S,3S)-Hydroxybupropion; GW-353,162
Routes of
administration		Oral
ATC code
  • none
Identifiers
  • (+)-(2S,3S)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO2
Molar mass255.74 g·mol−1
3D model (JSmol)
  • Clc1cccc(c1)[C@]2(O)OCC(N[C@H]2C)(C)C
  • 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+/m0/s1 checkY
  • Key:RCOBKSKAZMVBHT-TVQRCGJNSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Radafaxine (developmental code GW-353,162; also known as (2S,3S)-hydroxybupropion or (S,S)-hydroxybupropion[1]) is a norepinephrine–dopamine reuptake inhibitor (NDRI) which was under development by GlaxoSmithKline in the 2000s for a variety of different indications but was never marketed.[2] These uses included treatment of restless legs syndrome, major depressive disorder, bipolar disorder, neuropathic pain, fibromyalgia, and obesity.[2] Regulatory filing was planned for 2007,[3] but development was discontinued in 2006 due to "poor test results".[4]

Pharmacology

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Pharmacodynamics

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Radafaxine is described as a norepinephrine–dopamine reuptake inhibitor (NDRI). In contrast to bupropion, it appears to have a higher potency on inhibition of norepinephrine reuptake than on dopamine reuptake. Radafaxine has about 70% of the efficacy of bupropion in blocking dopamine reuptake, and 392% of efficacy in blocking norepinephrine reuptake, making it fairly selective for inhibiting the reuptake of norepinephrine over dopamine.[5][6] This, according to GlaxoSmithKline, may account for the increased effect of radafaxine on pain and fatigue.[7] At least one study suggests that radafaxine has a low abuse potential similar to bupropion.[8]

Chemistry

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Radafaxine is a potent metabolite of bupropion, the compound in GlaxoSmithKline's Wellbutrin. More specifically, hydroxybupropion is a major metabolite of bupropion that is further metabolized via an intramolecular cyclization to give radafaxine as the (2S,3S) isomer,[9] as well as the corresponding (2R,3R) isomer isomer, which is less pharmacologically active as a monoamine reuptake inhibitor than radafaxine.[10][11][12] Manifaxine (GW-320,659) was developed as an analogue of radafaxine and has been studied for the treatment of ADHD and obesity.[13][14]

See also

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References

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  1. ^ 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. Advances in Pharmacology. Vol. 69. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 9780124201187. PMID 24484978.
  2. ^ a b "Radafaxine - AdisInsight".
  3. ^ "Reviews Novel Therapeutics For CNS Disorders And Confirms Strong Pipeline Momentum". BioSpace. 23 November 2004. Archived from the original on 2007-09-28.
  4. ^ Kollewe J (27 July 2006). "GSK breakthrough on bird flu vaccine". Independent.co.uk. Archived from the original on 2007-10-01.
  5. ^ Xu H, Loboz KK, Gross AS, McLachlan AJ (March 2007). "Stereoselective analysis of hydroxybupropion and application to drug interaction studies". Chirality. 19 (3): 163–70. doi:10.1002/chir.20356. PMID 17167747.
  6. ^ Bondarev ML, Bondareva TS, Young R, Glennon RA (August 2003). "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology. 474 (1): 85–93. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199.
  7. ^ Burch D. "Neurosciences Development Portfolio" (PDF). Archived from the original (PDF) on 2007-09-28.
  8. ^ Volkow ND, Wang GJ, Fowler JS, Learned-Coughlin S, Yang J, Logan J, et al. (March 2005). "The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects". Biological Psychiatry. 57 (6): 640–6. doi:10.1016/j.biopsych.2004.12.007. PMID 15780851. S2CID 13313064.
  9. ^ Radafaxine at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  10. ^ Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors". Mol Pharmacol. 66 (3): 675–682. doi:10.1124/mol.104.001313. PMID 15322260.
  11. ^ Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI (June 2010). "Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation". J Med Chem. 53 (12): 4731–4748. doi:10.1021/jm1003232. PMC 2895766. PMID 20509659.
  12. ^ Carroll FI, Muresan AZ, Blough BE, Navarro HA, Mascarella SW, Eaton JB, Huang X, Damaj MI, Lukas RJ (March 2011). "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. doi:10.1021/jm1014555. PMC 3048909. PMID 21319801.
  13. ^ DeVeaugh-Geiss J, Conners CK, Sarkis EH, Winner PK, Ginsberg LD, Hemphill JM, et al. (August 2002). "GW320659 for the treatment of attention-deficit/hyperactivity disorder in children". Journal of the American Academy of Child and Adolescent Psychiatry. 41 (8): 914–20. doi:10.1097/00004583-200208000-00009. PMID 12162627.
  14. ^ Spraggs CF, Pillai SG, Dow D, Douglas C, McCarthy L, Manasco PK, et al. (December 2005). "Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects". Pharmacogenetics and Genomics. 15 (12): 883–9. doi:10.1097/01213011-200512000-00006. PMID 16272960. S2CID 40809351.
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