Cycloserine

Not to be confused with Cyclosarin.

Cycloserine

Systematic (IUPAC) name
(R)-4-Amino-1,2-oxazolidin-3-one
Clinical data
Trade names	Seromycin
AHFS/Drugs.com	monograph
Licence data	US FDA:link
Pregnancy category	C
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	~70% to 90%
Metabolism	Hepatic
Biological half-life	10 hrs (normal renal function)
Excretion	Renal
Identifiers
CAS Number	68-41-7 Y
ATC code	J04AB01 (WHO)
PubChem	CID: 6234
DrugBank	DB00260 Y
ChemSpider	5998 Y
UNII	95IK5KI84Z Y
KEGG	D00877 Y
ChEBI	CHEBI:40009 Y
ChEMBL	CHEMBL771 Y
NIAID ChemDB	007654
Chemical data
Formula	C3H6N2O2
Molecular mass	102.092 g/mol
SMILES O=C1NOC[C@H]1N
InChI InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 Y Key:DYDCUQKUCUHJBH-UWTATZPHSA-N Y
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Cycloserine (4-amino-3-isoxazolidinone) is an amino acid derivative with an unusual structure. It is a colorless solid that is produced by some bacteria. It has emerged as a drug sold under the brand name Seromycin. It is an antibiotic effective against Mycobacterium tuberculosis.

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

Tuberculosis

For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. 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). Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures. Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Psychiatry

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. Another review found priliminary evidence of benefit. Evidence for use in addiction is tentative but also unclear.

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria. 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). The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. 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. If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together. This effectively leads to inhibition of peptidoglycan synthesis.

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine. Cycloserine can be thought of a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.

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

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. The same team prepared the molecule synthetically. Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.

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. 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 having kept more control over pricing and ensuring that the philanthropic initiative continued to be met. According to a Lilly spokesperson, the company had no way to control the price of the drug after it was outlicensed due to antitrust laws.

Research

There is some experimental evidence to suggest that d-cycloserine aids in learning by helping form stronger neural connections.