title: A novel tertiary pyridostigmine derivative [3-(N,N-dimethylcarbamyloxy)-1-methyl-delta 3-tetrahydropyridine]: anticholinesterase properties and efficacy against soman.
abstract: In an effort to develop an effective centrally acting pretreatment compound against organophosphorus poisons, the tertiary pyridostigmine (Pyr) derivative 3-(N,N-dimethyl-carbamyloxy)-1-methyl-delta 3-tetrahydropyridine (THP) was synthesized and studied for its anticholinesterase properties, as well as its efficacy against soman intoxication in guinea pigs. Injection of THP (262 micrograms/kg, im) into adult male guinea pigs caused inhibition of blood (30%) and brain (25%) acetylcholinesterase (AChE), showing that THP penetrates the blood-brain barrier. Pyr (131 micrograms/kg, im) caused AChE inhibition in the blood (59%), but not in the brain. The inhibitory potencies of THP and Pyr were compared by determining their IC50 values for in vitro inhibition of both AChE (brain, erythrocyte) and pseudo-cholinesterase (plasma) in three mammalian species (guinea pig, rat, rabbit). THP, although effective in inhibiting both types of cholinesterase, was in general less potent than Pyr. Pretreatment of guinea pigs with THP (262 micrograms/kg, im) plus Pyr (131 micrograms/kg, im), 30 min prior to subcutaneous soman challenge, with no antimuscarinic or oxime treatment, protected 60% of the animals against 2 X LD50 of soman. Neither THP nor Pyr alone was effective. The protective pretreatment regimen did not prevent convulsions, but shortened the recovery time in surviving animals (median recovery time 1.6 hr, compared to 24 hr in control and other groups of animals pretreated with THP or Pyr alone). A combination of THP and Pyr thus appears to provide a means of evaluating the relative importance of selective peripheral plus central vs peripheral AChE protection against soman.
authors.affiliation: Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425.
authors.forename: R
authors.initials: R
authors.lastname: Ray
authors.forename: O E
authors.initials: OE
authors.lastname: Clark
authors.forename: K W
authors.initials: KW
authors.lastname: Ford
authors.forename: K R
authors.initials: KR
authors.lastname: Knight
authors.forename: L W
authors.initials: LW
authors.lastname: Harris
authors.forename: C A
authors.initials: CA
authors.lastname: Broomfield
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics; D006168:Guinea Pigs; D008297:Male; D015394:Molecular Structure; D011729:Pyridostigmine Bromide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000037:antagonists & inhibitors*
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; C069426:tetrahydropyridostigmine; D012999:Soman; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide