Chemistry:Cycloserine

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Short description: Tuberculosis medication
Cycloserine
Cycloserine.svg
Cycloserine ball-and-stick model.png
Clinical data
Trade namesSeromycin
Other namesD-cycloserine, 4-amino-3-isoxazolidinone
AHFS/Drugs.comMonograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~70% to 90%
MetabolismLiver
Elimination half-life10 hrs (normal kidney function)
ExcretionKidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC3H6N2O2
Molar mass102.093 g·mol−1
3D model (JSmol)
Melting point155 to 156 °C (311 to 313 °F) (dec.)
  (verify)

Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis.[1][2] Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis.[2] It is given by mouth.[2]

Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness.[2] It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics.[2] It is unclear if use during pregnancy is safe for the baby.[2] Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with the formation of the bacteria's cell wall.[2]

Cycloserine was discovered in 1954 from a type of Streptomyces.[3] It is on the World Health Organization's List of Essential Medicines.[4]

Medical uses

Tuberculosis

For the treatment of tuberculosis, cycloserine is classified as a second-line drug. Its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors).[5][6] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures.[6] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.[citation needed]

Psychiatry

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015.[7] Another review found preliminary evidence of benefit.[8] Evidence for use in addiction is tentative but also unclear.[9]

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria.[10][11] As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl).[11] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.[11] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules.[11] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined.[11] This effectively leads to inhibition of peptidoglycan synthesis.[11]

Psychiatric use is suggested based on partial NMDA receptor agonism, which improves neural plasticity in lab animals. The degree of clinical usefulness is, as aforementioned, very unclear and still being explored.[8]

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine.[12][13] Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.[citation needed]

Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.[12]

Synthesis

Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from DL‐β‐aminoxyalanine ethyl ester. In 1957, Platter et al. managed to synthesis the pure D-enantiomer by cyclizing the corresponding α‐amino‐β‐chlorohydroxamic acids. Chemical synthesis of the compound was revolutionized in the 2010s, when several approaches starting with the cheap D-serine (mirror form of normal L-serine) were published by different groups.[14]

The biosynthesis of the compound is defined by a ten-gene cluster. L-serine and L-arginine are converted to O-ureido-L-serine, flipped to O-ureido-D-serine, then turned into the final compound by cyclization. In 2013, Uda et al. successfully used recombinant versions of three enzymes in the cluster to produce the compound.[15]

A 1963 patent describes industrial production of the drug by bacterial fermentation.[16] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.[citation needed]

History

The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces.[17] The same team prepared the molecule synthetically.[18] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.[19]

Economics

In the U.S., the price of cycloserine increased from $500 for 30 pills to $10,800 in 2015 after the Chao Center for Industrial Pharmacy and Contract Manufacturing changed ownership to Rodelis Therapeutics in August 2015.[20]

The price increase was rescinded after the previous owner, the Purdue University Research Foundation, which retained "oversight of the manufacturing operation" intervened and Rodelis returned the drug to an NGO of Purdue University. The foundation now will charge $1,050 for 30 capsules, twice what it charged before". Eli Lilly has been criticised for not ensuring that the philanthropic initiative continued. Due to US antitrust laws, however, no company may control the price of a product after it is outlicensed.[21]

In 2015, the cost in the United States was increased to US$3,150 a month and then decreased to US$1,050 per month.[21]

Research

Some experimental evidence suggests that D-cycloserine aids in learning by helping form stronger neural connections.[22] It has been investigated as an aid to facilitate exposure therapy in people with PTSD and anxiety disorders,[23][24][25] and treatment with schizophrenia.[26] In a clinical trial, a course of D-cycloserine combined with a single dose of ketamine was investigated for treatment resistant bipolar depression. When administered for 8 weeks after a ketamine infusion, cycloserine appeared to potentiate the antidepressant effects in all trial participants.[27] However, a 2019 clinical trial showed no statistically significant difference between the D-cycloserine and placebo groups when it came to maintaining the antidepressant effect of a single ketamine infusion. The authors suggest several possible explanations for this nonsignificance, namely the inclusion of high-risk or severely treatment-resistant participants as well as a possible confounding carryover effect from the ketamine infusion phase. Although the results point to D-cycloserine having a stronger antisuicidal effect than placebo, the authors caution that this difference might be attributed to the placebo group feeling worse than the D-cycloserine feeling better.[28] A combination drug, cycloserine/lurasidone, containing D-cycloserine and the atypical antipsychotic lurasidone is being developed for acute suicidal ideation/behavior.[29]

References

  1. ↑ "L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats". Neuropharmacology (Elsevier BV) 25 (4): 411–418. April 1986. doi:10.1016/0028-3908(86)90236-4. PMID 3012401. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Cycloserine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/cycloserine.html. 
  3. ↑ (in en) Mechanism of Action. Springer Science & Business Media. 2012. p. 41. ISBN 9783642460517. https://books.google.com/books?id=xjPtCAAAQBAJ&pg=PA41. 
  4. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  5. ↑ "Consolidation of human motor cortical neuroplasticity by D-cycloserine". Neuropsychopharmacology 29 (8): 1573–8. August 2004. doi:10.1038/sj.npp.1300517. PMID 15199378. 
  6. ↑ 6.0 6.1 "CYCLOSERINE: Human Health Effects". National Institutes of Health. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+68-41-7. 
  7. ↑ "Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders". The Cochrane Database of Systematic Reviews 2015 (5): CD007803. May 2015. doi:10.1002/14651858.CD007803.pub2. PMID 25957940. 
  8. ↑ 8.0 8.1 "D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review". The International Journal of Neuropsychopharmacology 19 (4): pyv102. April 2016. doi:10.1093/ijnp/pyv102. PMID 26364274. 
  9. ↑ "D-cycloserine effects on extinction of conditioned responses to drug-related cues". Biological Psychiatry 71 (11): 947–55. June 2012. doi:10.1016/j.biopsych.2012.02.030. PMID 22579305. 
  10. ↑ "Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W". Journal of Bacteriology 110 (3): 978–87. June 1972. doi:10.1128/JB.110.3.978-987.1972. PMID 4555420. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine". The FEBS Journal 280 (4): 1150–66. February 2013. doi:10.1111/febs.12108. PMID 23286234. 
  12. ↑ 12.0 12.1 "Initial characterization of D-cycloserine for future formulation development for anxiety disorders". Drug Discoveries & Therapeutics 5 (5): 253–60. October 2011. doi:10.5582/ddt.2011.v5.5.253. PMID 22466372. 
  13. ↑ "An Aromatization Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase for the Antibiotic l-Cycloserine". Journal of the American Chemical Society 120 (10): 2256–2267. 1998. doi:10.1021/ja972907b. 
  14. ↑ "Principles of plastic surgery of congenital facial abnormalities". Facial Plastic Surgery 3 (3): 147–154. 6 December 2021. doi:10.1002/cmdc.202100503. PMID 3459696. 
  15. ↑ "Establishment of an in vitro D-cycloserine-synthesizing system by using O-ureido-L-serine synthase and D-cycloserine synthetase found in the biosynthetic pathway". Antimicrobial Agents and Chemotherapy 57 (6): 2603–2612. June 2013. doi:10.1128/AAC.02291-12. PMID 23529730. 
  16. ↑ "US3090730A Process for the production of cycloserine". 21 May 1963. https://patents.google.com/patent/US3090730A/en. 
  17. ↑ "D-4-Amino-3-isoxazolidinone, a new antibiotic". Journal of the American Chemical Society 77 (8): 2344–5. 1955. doi:10.1021/ja01613a105. 
  18. ↑ "Synthesis of D-4-amino-3-isoxazolidinone". Journal of the American Chemical Society 77 (8): 2346–7. 1955. doi:10.1021/ja01613a107. 
  19. ↑ "Structure and reactions of cycloserine". Journal of the American Chemical Society 77 (8): 2345–6. 1955. doi:10.1021/ja01613a106. 
  20. ↑ "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. 20 September 2015. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html?ref=health&_r=0. 
  21. ↑ 21.0 21.1 "Big Price Increase for Tuberculosis Drug Is Rescinded". NYT. 21 September 2015. https://www.nytimes.com/2015/09/22/business/big-price-increase-for-tb-drug-is-rescinded.html?_r=0. 
  22. ↑ "Learning and Brain Activity Are Boosted by a Dose of a Small-Molecule Compound". http://www.scientificamerican.com/article/learning-and-brain-activity-are-boosted-by-a-dose-of-a-small-molecule-compound/. 
  23. ↑ "An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials". Biological Psychiatry 78 (5): E15-27. September 2015. doi:10.1016/j.biopsych.2015.06.008. PMID 26238379. 
  24. ↑ "D-cycloserine as an augmentation strategy for cognitive behavioral therapy for anxiety disorders". Biology of Mood & Anxiety Disorders 3 (1): 11. May 2013. doi:10.1186/2045-5380-3-11. PMID 23768232. 
  25. ↑ "Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders". Pharmacology & Therapeutics 149: 150–90. May 2015. doi:10.1016/j.pharmthera.2014.12.004. PMID 25550231. 
  26. ↑ "D-cycloserine: an evolving role in learning and neuroplasticity in schizophrenia". Schizophrenia Bulletin 38 (5): 936–41. September 2012. doi:10.1093/schbul/sbs012. PMID 22368237. 
  27. ↑ "Single-Dose Ketamine Followed by Daily d-Cycloserine in Treatment-Resistant Bipolar Depression". The Journal of Clinical Psychiatry 76 (6): 737–738. June 2015. doi:10.4088/JCP.14l09527. PMID 26132675. https://www.psychiatrist.com/jcp/bipolar/single-dose-ketamine-followed-daily-d-cycloserine/. 
  28. ↑ "Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo-control study". Neuropsychopharmacology (Springer Nature) 44 (12): 2112–2118. November 2019. 2019-08-17. doi:10.1038/s41386-019-0480-y. PMID 31421635. 
  29. ↑ "Official page about NeuroRX NRX100/NRX101". http://www.neurorxpharma.com/nrx-100nrx-101-overview.html. 



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