Progabide
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| Trade names | Gabrene, Gabren |
| Other names | SL-76.002; SL-76002; SL76002; Halogabide |
| Routes of administration | Oral[1] |
| Drug class | GABA receptor agonist; GABAA and GABAB receptor agonist; GABA prodrug |
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| Pharmacokinetic data | |
| Metabolites | Progabide acid (SL-75.102), gabamide, GABA[1] |
| Elimination half-life | 10–12 hours[1] |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.057.872 |
| Chemical and physical data | |
| Formula | C17H16ClFN2O2 |
| Molar mass | 334.78 g·mol−1 |
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Progabide, sold under the brand name Gabrene, is a GABA receptor agonist which is used in the treatment of epilepsy.[1] It is an analogue of γ-aminobutyric acid (GABA) and acts both via a metabolite and as a prodrug of GABA, in turn behaving as an agonist of the GABA receptors.[2][3]
Uses
[edit]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.[4][3][additional citation(s) needed]
Side effects
[edit]Side effects of progabide include drowsiness, insomnia, and nausea.[1] Less frequent side effects have been reported to include diaphoresis, malaise, gastralgia, somnolence, pruritus, urticaria, darkening of urine, and elevated liver enzymes.[1] The drug has been associated with liver toxicity.[5]
Pharmacology
[edit]Progabide acts as a non-selective GABA receptor agonist, including of both the GABAA and GABAB receptors.[6][3][1][7][8] It is a GABA receptor agonist itself but also metabolizes into the more potent GABA receptor agonist progabide acid (SL-75.102).[6][3][1][2] In addition, progabide and progabide acid are metabolized into gabamide and γ-aminobutyric acid (GABA), which act as GABA receptor agonists as well.[6][1][2] Progabide crosses the blood–brain barrier, whereas gabamide and GABA do not, but progabide form gabamide and GABA within the brain.[6][1][2] The drug and its metabolites are selective for GABA receptors and do not interact with various other neurotransmitter receptors, nor do they affect GABA reuptake, GABA release, or GABA transaminase.[6][1] As such, progabide is a centrally active and pure GABA receptor agonist that acts in part via active metabolites including progabide acid, gabamide, and GABA.[6][1]
The drug produces anticonvulsant effects in animals, but findings in humans have been more mixed.[3][1][7][8] It is not known to produce some of the undesirable effects observed with other GABAA receptor agonists like muscimol such as myoclonus and psychological disturbances.[3] This might be partly due to the lower potency of progabide compared to muscimol.[3]
Progabide reaches peak levels after 2 to 3 hours with oral administration in humans.[1] Steady-state levels are reached after 2 to 4 days of repeated administration.[1] Its elimination half-life is 10 to 12 hours.[1] The drug is extensively metabolized, with only trace amounts of progabide being recovered in urine.[1][2]
Chemistry
[edit]Progabide is a synthetic compound defined as the Schiff base of γ-aminobutyramide and a substituted benzophenone.[1][2]
Synthesis
[edit]
History
[edit]Progabide was first described in the literature by at least 1979[6][9][10] and was introduced for medical use in France by 1985.[10] It was developed and marketed by Dausse-Synthelabo in France.[10][4] The drug was also in clinical trials in the United States and elsewhere in Europe, but ultimately does not appear to have been ever marketed outside of France.[1][4] Its adoption was limited by poor clinical effectiveness and incidence of liver toxicity.[5]
Society and culture
[edit]Names
[edit]Progabide is the generic name of the drug and its INN, USAN, BAN, and DCF.[9][4] It is also known by its former developmental code name SL-76.002 or SL-76002, by its brand name Gabrene or Gabren, and by its synonym halogabide.[9][4]
Availability
[edit]Progabide was marketed only in France as of 2000.[4][3]
Research
[edit]Progabide has been investigated for many conditions besides epilepsy, including Parkinson's disease, schizophrenia, clinical depression, anxiety disorders, and spasticity, with various levels of success.[1][additional citation(s) needed]
In 1987, Bartolini and colleagues reported progabide's actions on dopamine to be contradictory, decreasing dopamine release, dopamine receptor density and postsynaptic dopamine receptor responsivity while reducing striatal cholinergic activity so as to increase dopaminergic signaling.[11] Bartholini and colleagues concluded that it was this that caused Parkinson's patients in clinical trials to either see an improvement in their Parkinson's with a worsening of levodopa-induced dyskinesia or an improvement in dyskinesia but with sometimes aggravated Parkinson's symptoms.[11] 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.[12] 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."[13]
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.[14] 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.[15]
See also
[edit]- Tolgabide (SL-81.0142)
References
[edit]- ^ a b c d e f g h i j k l m n o p q r s t Bergmann KJ (1985). "Progabide: a new GABA-mimetic agent in clinical use". Clin Neuropharmacol. 8 (1): 13–26. doi:10.1097/00002826-198503000-00002. PMID 2983890.
Progabide, a new synthetic compound defined as the Schiff base of gamma-aminobutyramide and a substituted benzophenone, has been developed. Well absorbed, and relatively free of toxicity, it is both a direct GABA receptor agonist as well as an exogenous source of GABA. [...]
- ^ a b c d e f Shek, Efraim (1994). "Chemical delivery systems and prodrugs of anticonvulsive drugs". Advanced Drug Delivery Reviews. 14 (2–3): 227–241. doi:10.1016/0169-409X(94)90041-8.
Progabide (Fig. 6) is a GABA receptor agonist; however, it is also a pro-drug slowly releasing GABA [45]. The immediate onset of action is explained by the agonist properties of progabide while its ability to release GABA accounts for the duration of action. Chemically, progabide is a Schiff base obtained from γ-aminobutyramide and a substituted benzophenone. Man and animal metabolize progabide extensively. Only very small amounts of the administered drug can be found in urine [39]. Progabide can convert to the acid analog SL-75102 by hydrolysis, by oxidative deamination, or by transamination. By cleavage of the imine bond, progabide and SL-75102 can release GABA-mide or GABA, respectively. The enzymatic system capable of imine bond cleavage has not been identified. Yet it must be present, because both GABA and GABA-mide are found in the brain after administration of progabide to rats.
- ^ a b c d e f g h Taylor, Charles P. (1990). "GABA receptors and GABAergic synapses as targets for drug development". Drug Development Research. 21 (3): 151–160. doi:10.1002/ddr.430210302. ISSN 0272-4391. Retrieved 5 October 2025.
GABA PRODRUGS: Progabide was made as a prodrug of GABA and also has a metabolite that is a potent GABA agonist. It has anticonvulsant effects in several animal models [Bartholini et al., 1985; Morselli et al., 19861, but clinical trials have produced mixed results [Chadwick, 1990]. As of this writing, progabide is available only in France for treatment of seizures, and is of continued interest as a pharmacological tool. It is interesting that some of the undesired neurological and behavioral effects of GABA, agonists such as muscimol (myoclonus, psychological disturbances) have not been reported with progabide; this may partly be due to progabide's lower potency relative to muscimol.
- ^ a b c d e f Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Index nominum. Medpharm Scientific Publishers. p. 880. ISBN 978-3-88763-075-1. Retrieved 6 October 2025.
- ^ a b Perucca E, White HS, Bialer M (September 2023). "New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development". CNS Drugs. 37 (9): 781–795. doi:10.1007/s40263-023-01025-4. PMC 10501930. PMID 37603261.
Although many of the currently marketed [antiseizure medications (ASMs)] act on the GABA system (Table 1), only three of those, namely vigabatrin, tiagabine and ganaxolone, were rationally designed to exert a GABAergic effect. A fourth rationally designed compound, progabide, was developed in the 1980s as a GABA prodrug but never became established because of disappointing clinical efficacy results and the propensity to cause liver toxicity [101,102,103,104].
- ^ a b c d e f g Bartholini, G. (1981). "Present Knowledge of GABA Receptor Agonists". Medicinal Chemistry Advances. Elsevier. p. 345–353. doi:10.1016/b978-0-08-025297-1.50032-5. ISBN 978-0-08-025297-1. Retrieved 6 October 2025.
- ^ a b Paredes RG, Agmo A (1992). "GABA and behavior: the role of receptor subtypes". Neurosci Biobehav Rev. 16 (2): 145–170. doi:10.1016/s0149-7634(05)80177-0. PMID 1321392.
The mixed GABA-A-GABA-B agonist, progabide, has also shown limited success as an anticonvulsant. Although there are some reports describing clinically useful antiepileptic activity of this compound (197), high doses of progabide are required for significant reduction of symptoms in epileptic patients (187). Moreover, the attenuation of convulsive responses in animal models after progabide administration occurred only at doses that also produced sedation and ataxia (174,287).
- ^ a b Meldrum BS (1989). "GABAergic mechanisms in the pathogenesis and treatment of epilepsy". Br J Clin Pharmacol. 27 Suppl 1 (Suppl 1): 3S – 11S. doi:10.1111/j.1365-2125.1989.tb03454.x. PMC 1379672. PMID 2667605.
Progabide is a GABA receptor agonist acting on both GABAA and GABAB receptors, and is metabolised in the brain to yield SL 75102 (a more potent GABA agonist than progabide) and to GABA itself (Lloyd et al., 1982). It is by no means certain that progabide acts by enhancing GABAergic transmission: in some test systems it mimics the action of phenytoin rather than that of muscimol (Fromm et al., 1985). Progabide is anticonvulsant in a wide range of rodent models of epilepsy (Worms et al., 1982) and has some efficacy in man.
- ^ a b c Elks, J. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. ISBN 978-1-4757-2085-3. Retrieved 6 October 2025.
- ^ a b c "Progabide: world first Introduction of this anticonvulsant by Dausse-Synthelabo in France". InPharma. 515 (1): 19–20. 1985. doi:10.1007/BF03313499. ISSN 0156-2703. Retrieved 6 October 2025.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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)
- ^ 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.