 | |
| Clinical data | |
|---|---|
| Trade names | Gabrene, Gabren |
| Other names | SL-76.002; SL-76002; SL76002; Halogabide |
| Routes of administration | Oral[1] |
| Drug class | GABA receptor agonist;GABAA andGABAB receptoragonist;GABAprodrug |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Metabolites | Progabide acid (SL-75.102),gabamide,GABA[1] |
| Eliminationhalf-life | 10–12 hours[1] |
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.057.872 |
| Chemical and physical data | |
| Formula | C17H16ClFN2O2 |
| Molar mass | 334.78 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
| (verify) | |
Progabide, sold under the brand nameGabrene, is aGABA receptor agonist which is used in the treatment ofepilepsy.[1] It is ananalogue ofγ-aminobutyric acid (GABA) and acts both via ametabolite and as aprodrug of GABA, in turn behaving as anagonist of theGABA receptors.[2][3]
Progabide is approved inFrance for eithermonotherapy oradjunctive use in the treatment ofepilepsy—specifically,generalized tonic–clonic,myoclonic,partial, andLennox-Gastaut syndromeseizures—in both children and adults.[4][3][additional citation(s) needed]
Side effects of progabide includedrowsiness,insomnia, andnausea.[1] Less frequent side effects have been reported to includediaphoresis,malaise,gastralgia,somnolence,pruritus,urticaria,darkening of urine, andelevated liver enzymes.[1] The drug has been associated withliver toxicity.[5]
Progabide acts as anon-selectiveGABA receptor agonist, including of both theGABAA andGABAB receptors.[6][3][1][7][8] It is a GABA receptor agonist itself but alsometabolizes into the morepotent GABA receptor agonistprogabide acid (SL-75.102).[6][3][1][2] In addition, progabide and progabide acid are metabolized intogabamide andγ-aminobutyric acid (GABA), which act as GABA receptor agonists as well.[6][1][2] Progabide crosses theblood–brain barrier, whereas gabamide and GABA do not, but progabide form gabamide and GABA within the brain.[6][1][2] The drug and itsmetabolites areselective forGABA receptors and do not interact with various otherneurotransmitter receptors, nor do theyaffect GABA reuptake, GABArelease, orGABA transaminase.[6][1] As such, progabide is acentrally active and pure GABA receptor agonist that acts in part viaactive metabolites including progabide acid, gabamide, and GABA.[6][1]
The drug producesanticonvulsant 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 otherGABAA receptor agonists likemuscimol such asmyoclonus andpsychological disturbances.[3] This might be partly due to the lowerpotency of progabide compared to muscimol.[3]
Progabide reachespeak levels after 2 to 3 hours withoral administration in humans.[1]Steady-state levels are reached after 2 to 4 days of repeated administration.[1] Itselimination half-life is 10 to 12 hours.[1] The drug is extensively metabolized, with only trace amounts of progabide being recovered inurine.[1][2]
Progabide is asynthetic compound defined as theSchiff base ofγ-aminobutyramide and asubstituted benzophenone.[1][2]
Progabide was first described in the literature by at least 1979[6][9][10] and was introduced for medical use inFrance by 1985.[10] It was developed and marketed by Dausse-Synthelabo in France.[10][4] The drug was also inclinical trials in theUnited States and elsewhere inEurope, 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 ofliver toxicity.[5]
Progabide is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.[9][4] It is also known by its former developmental code nameSL-76.002 orSL-76002, by its brand nameGabrene orGabren, and by its synonymhalogabide.[9][4]
Progabide was marketed only inFrance as of 2000.[4][3]
Progabide has been investigated for manyconditions besides epilepsy, includingParkinson's disease,schizophrenia,clinical depression,anxiety disorders, andspasticity, with various levels of success.[1][additional citation(s) needed]
In 1987, Bartolini and colleagues reported progabide's actions ondopamine to be contradictory, decreasing dopaminerelease,dopamine receptordensity andpostsynaptic dopamine receptorresponsivity while reducingstriatalcholinergic activity so as to increasedopaminergicsignaling.[11] Bartholini and colleagues concluded that it was this that caused Parkinson's patients inclinical trials to either see an improvement in their Parkinson's with a worsening oflevodopa-induced dyskinesia or an improvement indyskinesia but with sometimes aggravatedParkinson's symptoms.[11] The cholinergic effect takes only a singleinjection to achieve in rats; when given withhaloperidol, the development oftolerance to haloperidol'scataleptic effects did not develop.[12] It was hoped that this would be effective fortardive dyskinesia. However, Soares, Rathbone and Deeks wrote in the 2004 issue ofThe Cochrane Database of Systematic Reviews that "Any possible benefits are likely to be outweighed by theadverse effects associated with their [GABAergic agents'] use."[13]
In addition to being tested forantipsychotic-induced tardive dyskinesia, progabide was itself tested as an antipsychotic; as early as 1979, it was obvious that it was ineffective forpsychosis.[14] While progabide may have been devoid of antipsychotic effects, it did have the effect inschizoaffective andhebephrenic patients of improving environmental responsiveness andsocial interactions.[15]
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. [...]
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.
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.
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].
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).
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.
