NMDA Receptor

Cycloserine is an analogue of the amino acid D-alanine with broad-spectrum antibiotic and glycinergic activities. D-cycloserine interferes with bacterial cell wall synthesis by competitively inhibiting two enzymes, L-alanine racemase and D-alanine:D-alanine ligase, thereby impairing peptidoglycan formation necessary for bacterial cell wall synthesis. This agent may be bactericidal or bacteriostatic, depending on its concentration at the infection site and the susceptibility of the organism. In addition, D-cycloserine is an excitatory amino acid and partial agonist at the glycine binding site of the NMDA receptor in the central nervous system (CNS); binding to the central NMDA receptor may result in amelioration of neuropathic pain.

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Cycloserine is an analog of the amino acid D-alanine. It interferes with an early step in bacterial cell wall synthesis in the cytoplasm by competitive inhibition of two enzymes, L-alanine racemase, which forms D-alanine from L-alanine, and D-alanylalanine synthetase, which incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation and bacterial cell wall synthesis.
Cycloserine is inhibitory for Mycobacterium tuberculosis in concentrations of 5 to 20 ug/ml in vitro. There is no cross-resistance between cycloserine and other tuberculostatic agents. While the antibiotic is effective in experimental infections caused by other microorganisms, studies in vitro reveal no suppression of growth in cultures made in conventional media, which contain D-alanine; this amino acid blocks the antibacterial activity of cycloserine. ... Cycloserine inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis. The use of media free of D-alanine reveals that the antibiotic inhibits the growth in vitro of enterococci, E. coli, Staph. aureus, Nocardia species, and Chlamydia.

Duration of the arctic transcranial direct current (tDCS)-induced increase in motor cortical excitability due to D-cycloserine. Excitability cannot be modulated by D-cycloserine alone [1]. Using modest levels of nicotine self-antenna systems, chronic D-cycloserine (40 mg/kg; 5 days/week; for 2 weeks) greatly reduces baseline nicotine; however, pollutants with larger baseline nicotine self-levels are still affected [3].

Absorption, Distribution and Excretion
Following oral administration, cycloserine is rapidly and almost completely (70% to 90%) absorbed from the gastrointestinal tract. The value of cycloserine lies in its ability to diffuse into cells and cross the blood-brain barrier, even in the absence of disease. After oral administration, 70% to 90% of cycloserine is rapidly absorbed. Peak plasma concentrations are reached 3 to 4 hours after a single dose; in children, peak plasma concentrations range from 20 to 35 μg/ml after a 20 mg/kg dose; only trace amounts of drug remain after 12 hours. Cycloserine is distributed in body fluids and tissues. The drug has virtually no blood-brain barrier effect; cerebrospinal fluid concentrations are approximately the same as plasma concentrations in all patients. Following injection, approximately 50% of cycloserine is excreted unchanged in the urine within the first 12 hours; a total of 65% of cycloserine is recovered in its active form within 72 hours. Metabolism/Metabolites Approximately 35% of the antibiotic is metabolized into unidentified substances.

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Biological Half-Life
The half-life in patients with normal kidney function is 10 hours, while the half-life is prolonged in patients with impaired kidney function.
Normal kidney function - 10 hours. Impaired kidney function - prolonged.

Hepatotoxicity
Cycloserine has been reported to be associated with a low incidence of elevated serum transaminases, which are usually transient, asymptomatic, and do not require dose adjustment. Cycloserine is often used in combination with drugs more clearly associated with liver dysfunction, while it itself usually has little or no effect on these abnormalities. Cycloserine has not been definitively proven to be associated with clinically significant liver injury, but it is frequently used in combination with known hepatotoxic drugs, so its potential effect cannot be completely ruled out. Probability Score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Limited information from an early study suggests that a pregnant woman taking 1 gram of cycloserine daily may produce moderate levels of cycloserine in breast milk. This is not a reason to discontinue breastfeeding if the mother needs to take cycloserine, especially if the infant is older than 2 months. If this medication is taken while breastfeeding, exclusively breastfed infants should be monitored, and serum drug concentrations may be measured if necessary to rule out toxicity.
◉ Effects on Breastfed Infants
No adverse reactions were observed in 5 breastfed infants (age not specified). The mothers of these infants took 250 mg of cycloserine orally four times daily.
Five women with multidrug-resistant tuberculosis received multidrug therapy; four of them took cycloserine during pregnancy and postpartum, and one only postpartum. All of these infants were breastfed (feeding extent and duration not specified). These children were developmentally normal at 1.25, 1.8, 3.9, 4.6, and 5.5 years of age; only one child had mild language delay, and another had ADHD.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

[1]. Consolidation of human motor cortical neuroplasticity by D-cycloserine. Neuropsychopharmacology, 2004. 29(8): p. 1573-8.
[2]. Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine. Nat Commun. 2017 Dec 5;8(1):1939.
[3]. D-cycloserine selectively decreases nicotine self-administration in rats with low baseline levels of response. Pharmacol Biochem Behav, 2011. 98(2): p. 210-4.

D-Cycloserine is a 4-amino-1,2-oxazolidin-3-one with an R configuration. It is an antibiotic produced by Streptomyces garyphalus or Streptomyces orchidaceus, commonly used in multidrug regimens for tuberculosis to treat tuberculosis that has developed resistance or toxicity to first-line drugs. As an analogue of D-alanine, D-Cycloserine interferes with bacterial cell wall synthesis in the cytoplasm by competitively inhibiting L-alanine racemic enzyme (catalyzing the conversion of L-alanine to D-alanine) and D-alanine-D-alanine ligase (incorporating D-alanine into the pentapeptides required for peptidoglycan formation and bacterial cell wall synthesis). D-Cycloserine possesses multiple functions, including anti-tuberculosis, anti-infective, anti-metabolic, metabolic, and NMDA receptor agonist effects. It is an organic-oxygen heterocyclic antibiotic, an organic-nitrogen heterocyclic antibiotic, and a 4-amino-1,2-oxazolidin-3-one. It is the conjugate base of D-Cycloserine (1+). It is the enantiomer of L-cycloserine. It is the zwitterion tautomer of D-cycloserine. It is an antibiotic produced by Streptomyces garyphalus. Cycloserine is a broad-spectrum antibiotic used as a second-line treatment for drug-resistant tuberculosis, often in combination with other anti-tuberculosis drugs. Cycloserine appears to have little hepatotoxicity, but it is often used in combination with drugs known to be hepatotoxic, so its role in reported cases of liver injury due to combination therapy cannot be completely ruled out. Cycloserine has been reported to be present in Streptomyces garyphalus and Streptomyces lavendulae, and relevant data are available. Cycloserine is an analogue of the amino acid D-alanine and possesses broad-spectrum antibacterial and glycineric activity. D-Cycloserine impairs the formation of peptidoglycan, a necessary component for bacterial cell wall synthesis, by competitively inhibiting two enzymes—L-alanine racemic enzyme and D-alanine:D-alanine ligase. Depending on its concentration at the site of infection and the susceptibility of the pathogen, this drug may have bactericidal or bacteriostatic effects. Furthermore, D-Cycloserine is an excitatory amino acid and a partial agonist of the glycine-binding site of NMDA receptors in the central nervous system (CNS); binding to central NMDA receptors may alleviate neuropathic pain. It is an antibiotic substance produced by Streptomyces garyphalus. Drug Indications It can be used in combination with up to five other drugs for the treatment of Mycobacterium avium complex (MAC) infections and also for the treatment of tuberculosis (TB). Mechanism of Action Cycloserine is an analogue of the amino acid D-alanine. It interferes with early steps of bacterial cell wall synthesis in the cytoplasm by competitively inhibiting two enzymes—L-alanine racemase (which converts L-alanine to D-alanine) and D-alanylalanine synthase (which incorporates D-alanine into the pentapeptides required for peptidoglycan formation and bacterial cell wall synthesis). Tuberculosis patients treated with clinical doses of D-cycloserine show increased excretion of β-alanine and D-β-aminoisobutyric acid. Cycloserine has inhibitory effects on Mycobacterium tuberculosis at in vitro concentrations of 5 to 20 μg/ml. There is no cross-resistance between cycloserine and other anti-tuberculosis drugs. Although this antibiotic is effective against experimental infections caused by other microorganisms, in vitro studies have shown that bacteria cultured in conventional media containing D-alanine do not exhibit growth inhibition; D-alanine blocks the antibacterial activity of cycloserine. …Cycloserine inhibits D-alanine-mediated bacterial cell wall synthesis. Using a D-alanine-free culture medium, the antibiotic inhibited the growth of Enterococcus, Escherichia coli, Staphylococcus aureus, Nocardia spp., and Chlamydia trachomatis in vitro.

C3H6N2O2

102.09

102.042

C, 35.29; H, 5.92; N, 27.44; O, 31.34

68-41-7

D-Cycloserine (Standard);68-41-7

6234

White to off-white solid powder

1.3±0.1 g/cm3

267ºC

147ºC

1.475

-1.84

2

3

0

7

92.9

1

C1[C@H](C(=O)NO1)N

DYDCUQKUCUHJBH-UWTATZPHSA-N

InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1

(4R)-4-amino-1,2-oxazolidin-3-one

Seromycin; Cycloserine; D-cycloserine; 68-41-7; Seromycin; orientomycin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~25 mg/mL (~244.88 mM)
DMSO : ~1 mg/mL (~9.80 mM)

Solubility in Formulation 1: 11.11 mg/mL (108.83 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)