FUNDAMENTAL AND APPLIED TOXICOLOGY 6, 506-514 (1986) Kinetic Studies and Structure-Activity Relationships of Bispyridinium Oximes as Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Compounds

Toxicol. 6,506-514. The kinetics of the reactivation of acetylcholinesterase inhibited by isopropyl methylphosphonofluoridate was studied. The reactivators used include nine bispyridinium monooximes and three bispyridinium dioximes. The dissociation constant (KJ) and the rate constant (fcj of dephosphonyiation of the complex formed from the organophosphorus acetylcholinesterase (OP-AChE) and the oxime were measured. The reactivation parameters obtained from the in vitro kinetic studies were used to elucidate the structure-activity relationships. The hydrophobic property of a nonoxime substituent at the 3-position on the pyridinium ring can exert a positive effect on their binding affinity to OP-AChE. However, the rate constants (k2) of the nuclcophilic displacement of OP-AChE by oximes depend negatively on these physical and structural factors of the oximes. The correlations of the in vivo antidotal efficacy (ED50) of these bispyridinium oximes have been analyzed with their pharmacological properties, e.g., reactivation potency, an-timuscarinic activities, and antinicotinic activities. However, no satisfactory correlations were observed. It may be concluded that the detoxication mechanism of poisoning by isopropyl meth-ylphosphonofluoridate is different from those of pinacolyl methylphosphonofluoridate and para-OXOn. C 1986 Society of Tojucotofy