Synthesis and preliminary biological evaluation of gabactyzine, a benactyzine-GABA mutual prodrug, as an organophosphate antidote.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
27 10 2022
27 10 2022
Historique:
received:
11
07
2022
accepted:
25
10
2022
entrez:
27
10
2022
pubmed:
28
10
2022
medline:
1
11
2022
Statut:
epublish
Résumé
Organophosphates (OPs) are inhibitors of acetylcholinesterase and have deleterious effects on the central nervous system. Clinical manifestations of OP poisoning include convulsions, which represent an underlying toxic neuro-pathological process, leading to permanent neuronal damage. This neurotoxicity is mediated through the cholinergic, GABAergic and glutamatergic (NMDA) systems. Pharmacological interventions in OP poisoning are designed to mitigate these specific neuro-pathological pathways, using anticholinergic drugs and GABAergic agents. Benactyzine is a combined anticholinergic, anti-NMDA compound. Based on previous development of novel GABA derivatives (such as prodrugs based on perphenazine for the treatment of schizophrenia and nortriptyline against neuropathic pain), we describe the synthesis and preliminary testing of a mutual prodrug ester of benactyzine and GABA. It is assumed that once the ester crosses the blood-brain-barrier it will undergo hydrolysis, releasing benactyzine and GABA, which are expected to act synergistically. The combined release of both compounds in the brain offers several advantages over the current OP poisoning treatment protocol: improved efficacy and safety profile (where the inhibitory properties of GABA are expected to counteract the anticholinergic cognitive adverse effects of benactyzine) and enhanced chemical stability compared to benactyzine alone. We present here preliminary results of animal studies, showing promising results with early gabactyzine administration.
Identifiants
pubmed: 36302937
doi: 10.1038/s41598-022-23141-9
pii: 10.1038/s41598-022-23141-9
pmc: PMC9613653
doi:
Substances chimiques
Benactyzine
595EG71R3F
Antidotes
0
Prodrugs
0
Organophosphates
0
Acetylcholinesterase
EC 3.1.1.7
Chemical Warfare Agents
0
Cholinergic Antagonists
0
Esters
0
gamma-Aminobutyric Acid
56-12-2
Cholinesterase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18078Informations de copyright
© 2022. The Author(s).
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