Progabide

{{Short description|Pharmaceutical drug}} {{Drugbox | Watchedfields = changed | verifiedrevid = 464215284 | image = Progabide structure.svg | image_class = skin-invert-image | width =

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 62666-20-0 | ATC_prefix = N03 | ATC_suffix = AG05 | ATC_supplemental = | PubChem = 5361323 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00837 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 10442693 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 38C836J57Z | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 287631 | synonyms = SL-76.002; SL-76002; SL76002; Halogabide

| IUPAC_name = 4-[(4-Chlorophenyl)-(5-fluoro-2-hydroxy-phenyl)-methylidene]aminobutanamide | C=17 | H=16 | Cl=1 | F=1 | N=2 | O=2 | SMILES = Clc1ccc(cc1)/C(=N\CCCC(N)=O)c2cc(F)ccc2O | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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+ | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = IBALRBWGSVJPAP-HEHNFIMWSA-N }}

'''Progabide''', sold under the brand name '''Gabrene''', is a GABA receptor agonist which is used in the treatment of epilepsy.<ref name="Bergmann1985">{{cite journal | vauthors = Bergmann KJ | title = Progabide: a new GABA-mimetic agent in clinical use | journal = Clin Neuropharmacol | volume = 8 | issue = 1 | pages = 13–26 | date = 1985 | pmid = 2983890 | doi = 10.1097/00002826-198503000-00002 | url = | quote = 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. [...]}}</ref> 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.<ref name="Shek1994">{{cite journal | last=Shek | first=Efraim | title=Chemical delivery systems and prodrugs of anticonvulsive drugs | journal=Advanced Drug Delivery Reviews | volume=14 | issue=2-3 | date=1994 | doi=10.1016/0169-409X(94)90041-8 | pages=227–241 | quote=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.}}</ref><ref name="Taylor1990">{{cite journal | last=Taylor | first=Charles P. | title=GABA receptors and GABAergic synapses as targets for drug development | journal=Drug Development Research | volume=21 | issue=3 | date=1990 | issn=0272-4391 | doi=10.1002/ddr.430210302 | pages=151–160 | url=https://onlinelibrary.wiley.com/doi/10.1002/ddr.430210302 | access-date=5 October 2025 | quote=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.| url-access=subscription }}</ref>

==Uses== Progabide was 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.<ref name="IndexNominum2000" /><ref name="Taylor1990" />{{Additional citation needed|date=October 2025}}.. it was completely withdrawn in France in 1999 <ref> https://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=65230401 </ref> because of its high Hepatotoxicity <ref> https://pharmacomedicale.org/medicaments/par-specialites/item/anti-epileptiques-les-points-essentiels </ref>

==Side effects== Side effects of progabide include drowsiness, insomnia, and nausea.<ref name="Bergmann1985" /> Less frequent side effects have been reported to include diaphoresis, malaise, gastralgia, somnolence, pruritus, urticaria, darkening of urine, and elevated liver enzymes.<ref name="Bergmann1985" /> The drug has been associated with liver toxicity.<ref name="PeruccaWhiteBialer2023" />

==Pharmacology== Progabide acts as a non-selective GABA receptor agonist, including of both the GABAA and GABAB receptors.<ref name="Bartholini1981" /><ref name="Taylor1990" /><ref name="Bergmann1985" /><ref name="ParadesAgmo1992">{{cite journal | vauthors = Paredes RG, Agmo A | title = GABA and behavior: the role of receptor subtypes | journal = Neurosci Biobehav Rev | volume = 16 | issue = 2 | pages = 145–170 | date = 1992 | pmid = 1321392 | doi = 10.1016/s0149-7634(05)80177-0 | url = | quote = 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).}}</ref><ref name="Meldrum1989">{{cite journal | vauthors = Meldrum BS | title = GABAergic mechanisms in the pathogenesis and treatment of epilepsy | journal = Br J Clin Pharmacol | volume = 27 Suppl 1 | issue = Suppl 1 | pages = 3S–11S | date = 1989 | pmid = 2667605 | pmc = 1379672 | doi = 10.1111/j.1365-2125.1989.tb03454.x | url = | quote = 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.}}</ref> It is a GABA receptor agonist itself but also metabolizes into the more potent GABA receptor agonist progabide acid (SL-75.102).<ref name="Bartholini1981" /><ref name="Taylor1990" /><ref name="Bergmann1985" /><ref name="Shek1994" /> In addition, progabide and progabide acid are metabolized into gabamide and γ-aminobutyric acid (GABA), which act as GABA receptor agonists as well.<ref name="Bartholini1981" /><ref name="Bergmann1985" /><ref name="Shek1994" /> Progabide crosses the blood–brain barrier, whereas gabamide and GABA do not, but progabide form gabamide and GABA within the brain.<ref name="Bartholini1981" /><ref name="Bergmann1985" /><ref name="Shek1994" /> 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.<ref name="Bartholini1981" /><ref name="Bergmann1985" /> 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.<ref name="Bartholini1981" /><ref name="Bergmann1985" />

The drug produces anticonvulsant effects in animals, but findings in humans have been more mixed.<ref name="Taylor1990" /><ref name="Bergmann1985" /><ref name="ParadesAgmo1992" /><ref name="Meldrum1989" /> 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.<ref name="Taylor1990" /> This might be partly due to the lower potency of progabide compared to muscimol.<ref name="Taylor1990" />

Progabide reaches peak levels after 2 to 3{{nbsp}}hours with oral administration in humans.<ref name="Bergmann1985" /> Steady-state levels are reached after 2 to 4{{nbsp}}days of repeated administration.<ref name="Bergmann1985" /> Its elimination half-life is 10 to 12{{nbsp}}hours.<ref name="Bergmann1985" /> The drug is extensively metabolized, with only trace amounts of progabide being recovered in urine.<ref name="Bergmann1985" /><ref name="Shek1994" />

==Chemistry== Progabide is a synthetic compound defined as the Schiff base of γ-aminobutyramide and a substituted benzophenone.<ref name="Bergmann1985" /><ref name="Shek1994" />

===Synthesis=== thumb|center|800px|class=skin-invert-image|Progabide synthesis: C Berthier, J. P. Allaigre, and J. Debois, French Demande, {{Cite patent|country=FR|number=2553763}} (1985).

==History== Progabide was first described in the literature by at least 1979<ref name="Bartholini1981">{{cite book | last=Bartholini | first=G. | title=Medicinal Chemistry Advances | chapter=Present Knowledge of GABA Receptor Agonists | publisher=Elsevier | date=1981 | isbn=978-0-08-025297-1 | doi=10.1016/b978-0-08-025297-1.50032-5 | url=https://linkinghub.elsevier.com/retrieve/pii/B9780080252971500325 | access-date=6 October 2025 | page=345–353}}</ref><ref name="Elks2014" /><ref name="InPharma1985" /> and was introduced for medical use in France by 1985.<ref name="InPharma1985">{{cite journal | title=Progabide: world first Introduction of this anticonvulsant by Dausse-Synthelabo in France | journal=InPharma | volume=515 | issue=1 | date=1985 | issn=0156-2703 | doi=10.1007/BF03313499 | pages=19–20 | url=http://link.springer.com/10.1007/BF03313499 | access-date=6 October 2025| url-access=subscription }}</ref> It was developed and marketed by Dausse-Synthelabo in France.<ref name="InPharma1985" /><ref name="IndexNominum2000" /> 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.<ref name="Bergmann1985" /><ref name="IndexNominum2000" /> Its adoption was limited by poor clinical effectiveness and incidence of liver toxicity.<ref name="PeruccaWhiteBialer2023">{{cite journal | vauthors = Perucca E, White HS, Bialer M | title = New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development | journal = CNS Drugs | volume = 37 | issue = 9 | pages = 781–795 | date = September 2023 | pmid = 37603261 | pmc = 10501930 | doi = 10.1007/s40263-023-01025-4 | url = | quote = 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].}}</ref>

==Society and culture== ===Names=== ''Progabide'' is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|USAN|United States Adopted Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}.<ref name="Elks2014">{{cite book | last=Elks | first=J. | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer | date=14 November 2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&newbks=1&newbks_redir=0&lpg=PA1024&dq=progabide%2520INN&pg=PA1024#v=onepage&q=progabide%2520INN&f=false | access-date=6 October 2025 | page=}}</ref><ref name="IndexNominum2000">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | series=Index nominum | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA880 | access-date=6 October 2025 | page=880}}</ref> 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''.<ref name="Elks2014" /><ref name="IndexNominum2000" />

===Availability=== Progabide was marketed only in France as of 2000.<ref name="IndexNominum2000" /><ref name="Taylor1990" />

==Research== 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.<ref name="Bergmann1985" />{{Additional citation needed|date=October 2025}}

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.<ref name="Bartholini_et_al_1987">{{cite journal | vauthors = Bartholini G, Scatton B, Zivkovic B, Lloyd KG | title = GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease | journal = Advances in Neurology | year = 1987 | volume = 45 | pages = 79–83 | pmid = 3030072 }}</ref> 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.<ref name="Bartholini_et_al_1987"/> 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.<ref name=Bartholini_et_al_1980>{{cite journal | vauthors = Bartholini G, Scatton B, Zivkovic B | title = Effect of the new gamma-aminobutyric acid agonist SL 76 002 on striatal acetylcholine: relation to neuroleptic-induced extrapyramidal alterations | journal = Advances in Biochemical Psychopharmacology | volume = 24 | pages = 207–13 | year = 1980 | pmid = 6105775 }}</ref> 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."<ref name=bust_for_TD>{{cite journal | vauthors = Soares K, Rathbone J, Deeks J | title = Gamma-aminobutyric acid agonists for neuroleptic-induced tardive dyskinesia | journal = The Cochrane Database of Systematic Reviews | issue = 4 | article-number = CD000203 | date = October 2004 | pmid = 15494993 | doi = 10.1002/14651858.CD000203.pub2 | url = http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000203/frame.html | editor1-last = Soares-Weiser | editor1-first = Karla | url-access = subscription }}</ref>

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.<ref name=Bartholini_1979>{{cite journal | vauthors = Bartholini G | title = [Potential therapeutic activity of GABA-mimetic drugs in neuropsychiatry] | journal = Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie = Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie | volume = 125 | issue = 2 | pages = 265–9 | year = 1979 | pmid = 45343 }} (French)</ref> 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.<ref name=Lloyd_et_al_1983>{{cite journal | vauthors = Lloyd KG, Morselli PL, Depoortere H, Fournier V, Zivkovic B, Scatton B, Broekkamp C, Worms P, Bartholini G | display-authors = 6 | title = The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials | journal = Pharmacology, Biochemistry, and Behavior | volume = 18 | issue = 6 | pages = 957–66 | date = June 1983 | pmid = 6351106 | doi = 10.1016/S0091-3057(83)80021-5 | s2cid = 21297834 }}</ref>

==See also== * GABA receptor agonist * Tolgabide (SL-81.0142)

==References== {{Reflist}}

Category:4-Chlorophenyl compounds Category:Anticonvulsants Category:GABA analogues Category:GABAA receptor agonists Category:GABAA-rho receptor agonists Category:GABAB receptor agonists Category:Fluorobenzene derivatives Category:Imines Category:Neurotransmitter precursors Category:Phenols Category:Prodrugs