Progabide

Progabide (INN; trade name Gabrene, Sanofi-Aventis) is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABA_A, GABA_B, and GABA_A-ρ receptors.

Progabide

Clinical data
Routes of administration	Oral
ATC code	N03AG05 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	60%
Protein binding	95%
Metabolism	Hepatic
Elimination half-life	4 hours
Excretion	Renal
Identifiers
IUPAC name 4-[(4-Chlorophenyl)-(5-fluoro-2-hydroxy-phenyl)-methylidene]aminobutanamide
CAS Number	62666-20-0 Y
PubChem CID	5361323
DrugBank	DB00837 Y
ChemSpider	10442693 Y
UNII	38C836J57Z
ChEMBL	ChEMBL287631 Y
CompTox Dashboard (EPA)	DTXSID00878140
ECHA InfoCard	100.057.872
Chemical and physical data
Formula	C17H16ClFN2O2
Molar mass	334.78 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1ccc(cc1)/C(=N\CCCC(N)=O)c2cc(F)ccc2O
InChI InChI=1S/C17H16ClFN2O2/c18-12-5-3-11(4-6-12)17(21-9-1-2-16(20)23)14-10-13(19)7-8-15(14)22/h3-8,10,22H,1-2,9H2,(H2,20,23)/b21-17+ Y Key:IBALRBWGSVJPAP-HEHNFIMWSA-N Y
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Uses

Progabide is approved in France for either monotherapy or adjunctive use in the treatment of epilepsy—specifically, generalized tonic-clonic, myoclonic, partial, and Lennox-Gastaut syndrome seizures—in both children and adults.

Progabide has been investigated for many diseases besides epilepsy, including Parkinson's disease, schizophrenia, clinical depression, anxiety disorder and spasticity with various levels of success.

In 1987, Bartolini and colleagues reported progabide's actions on dopamine to be contradictory, decreasing dopamine release, dopamine receptor density and postsynaptic receptor responsivity to dopamine while reducing striatal cholinergic activity so as to increase dopaminergic effects.^[1] Bartholini and colleagues concluded that it was this that caused Parkinson's patients in human clinical trials to either see an improvement in their Parkinson's with a worsening of L-dopa dyskinesia or an improvement in dyskinesia but with sometimes aggravated Parkinson's symptoms.^[1] The cholinergic effect takes only a single injection to achieve in rats; when given with haloperidol, the development of tolerance to haloperidol's cataleptic effects did not develop.^[2] It was hoped that this would be effective for tardive dyskinesia. However, Soares, Rathbone and Deeks wrote in the 2004 issue of The Cochrane Database of Systematic Reviews that "Any possible benefits are likely to be outweighed by the adverse effects associated with their [GABAergic agents'] use."^[3]

In addition to being tested for antipsychotic-induced tardive dyskinesia, progabide was itself tested as an antipsychotic; as early as 1979, it was obvious that it was ineffective for psychosis.^[4] While progabide may have been devoid of antipsychotic effects, it did have the effect in schizoaffective and hebephrenic patients of improving environmental responsiveness and social interactions.^[5]

Synthesis

Progabide synthesis: C Berthier, J. P. Allaigre, and J. Debois, French Demande, FR 2553763 (1985).

See also

• Progabide acid (SL-75102), an active metabolite of progabide
• Tolgabide

References

1. Bartholini G, Scatton B, Zivkovic B, Lloyd KG (1987). "GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease". Advances in Neurology. 45: 79–83. PMID 3030072.
2. Bartholini G, Scatton B, Zivkovic B (1980). "Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations". Advances in Biochemical Psychopharmacology. 24: 207–13. PMID 6105775.
3. Soares K, Rathbone J, Deeks J (October 2004). Soares-Weiser K (ed.). "Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia". The Cochrane Database of Systematic Reviews (4): CD000203. doi:10.1002/14651858.CD000203.pub2. PMID 15494993.
4. Bartholini G (1979). "[Potential therapeutic activity of GABA-mimetic drugs in neuropsychiatry]". Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie = Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie. 125 (2): 265–9. PMID 45343. (French)
5. Lloyd KG, Morselli PL, Depoortere H, Fournier V, Zivkovic B, Scatton B, et al. (June 1983). "The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials". Pharmacology, Biochemistry, and Behavior. 18 (6): 957–66. doi:10.1016/S0091-3057(83)80021-5. PMID 6351106. S2CID 21297834.