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.