Chemistry:Radafaxine
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
Pharmacodynamics
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
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
- (2R,3R)-Hydroxybupropion
- 3-Chlorophenmetrazine
- Manifaxine
References
- ↑ "Bupropion and Bupropion Analogs as Treatments for CNS Disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. 69. 2014. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 9780124201187.
- ↑ 2.0 2.1 "Radafaxine - AdisInsight". https://adisinsight.springer.com/drugs/800017221.
- ↑ "Reviews Novel Therapeutics For CNS Disorders And Confirms Strong Pipeline Momentum". BioSpace. 23 November 2004. http://www.biospace.com/news_story.aspx?StoryID=18222420&full=1.
- ↑ Kollewe, Julia (27 July 2006). "GSK breakthrough on bird flu vaccine". Independent.co.uk. http://news.independent.co.uk/business/news/article1199374.ece#10919204097707524565.
- ↑ "Stereoselective analysis of hydroxybupropion and application to drug interaction studies". Chirality 19 (3): 163–70. March 2007. doi:10.1002/chir.20356. PMID 17167747.
- ↑ "Behavioral and biochemical investigations of bupropion metabolites". European Journal of Pharmacology 474 (1): 85–93. August 2003. doi:10.1016/S0014-2999(03)02010-7. PMID 12909199.
- ↑ Burch, Daniel. "Neurosciences Development Portfolio". http://213.219.8.102/pdfs/gsk/cns_seminar/353162.pdf.
- ↑ "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. March 2005. doi:10.1016/j.biopsych.2004.12.007. PMID 15780851.
- ↑ Radafaxine at the US National Library of Medicine Medical Subject Headings (MeSH)
- ↑ "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. doi:10.1124/mol.104.001313. PMID 15322260.
- ↑ "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. doi:10.1021/jm1003232. PMID 20509659.
- ↑ "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. doi:10.1021/jm1014555. PMID 21319801.
- ↑ "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. August 2002. doi:10.1097/00004583-200208000-00009. PMID 12162627.
- ↑ "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. December 2005. doi:10.1097/01213011-200512000-00006. PMID 16272960.
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