Pyridine and Pyridinium Electrophiles for Re-activation of Aged Acetylcholine Esterase
TS-036739 — Synthesis of molecules that will enable the aged form of acetylcholine esterase (AChE) to be re-alkylated and re-activated
Organophosphorus (OP) compounds containing a phosphoryl group have been used as pesticides and chemical warfare agents. These compounds are toxic due to their inhibition of the enzyme acetylcholinesterase (AChE), a serine hydrolase typically found in the central and peripheral nervous system that …
Organophosphorus (OP) compounds containing a phosphoryl group have been used as pesticides and chemical warfare agents. These compounds are toxic due to their inhibition of the enzyme acetylcholinesterase (AChE), a serine hydrolase typically found in the central and peripheral nervous system that regulates concentrations of the neurotransmitter acetylcholine. When the central phosphorus atom is attacked by the catalytic serine, a leaving group is substituted, leaving a phosphyl group covalently attached to the serine, which blocks the active site. Inhibition of AChE can lead to death by respiratory failure due to overstimulation of muscarinic acetylcholine receptors at the neuromuscular junctions. If left untreated after OP inhibition, the O-alkyl group of the AChE-OP adduct can undergo a dealkylation reaction, leaving a phosphonate (or phosphate) anion in the AChE active site in a process known as “aging”. The rate of aging varies from minutes to hours between different OPs. Currently there is no known therapeutic to reactivate aged AChE.
Researchers at The Ohio State University, led by Dr. Christopher Hadad, have developed a family of pyridine and pyridinium electrophiles (quinone methide precursors). The structures of these electrophiles are mimics of edrophonium, an oxyanilinium-based inhibitor of AChE that is known to bind in the active site. These electrophiles have been shown to possess highly tunable reactivity through modification of substituents on the pyridine scaffold or attached leaving groups. These electrophiles will be used to re-alkylate aged AChE to form stable alkylphosphonate AChE adducts that can be reactivated with conventional oximes or potentially self-reactivate.
- Reversal of neuromuscular block
- Target promoted alkylation
- Biochemistry therapeutics
- Reactivated with conventional oxides or potentially can self-reactivate