© 1991 Oxford University Press
other |
A Novel Tertiary Pyridostigmine Derivative [3-N,N-Dimethylcarbamyloxy)-1-Methyl-
3-Tetrahydropyridine]: Anticholinesterase Properties and Efficacy against Soman1
Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense Aberdeen Proving Ground, Maryland 21010–5425
Received February 28, 1990; accepted October 1, 1990
In an effort to develop an effective centrally acting pretreatment compound against organophosphorus poisons, the tertiary pyridostigmine (Pyr) derivative 3-(N,N-dimethyI-carbamyloxy)-l-methyl-
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 µg/kg, im) into adult male guinea pigs caused inhibition of Wood (30%) and brain (25%) acetylcholinesterase (AChE), showing that THP penetrates the blood-brain barrier. Pyr (131 µg/kg, im) caused AChE inhibition in the Hood (59%), but not in the brain. The inhibitory potencies of THP and Pyr were compared by determining their IC50 values for in vitroinhibition 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 µg/kg, im) plus Pyr (131 µg/kg, im). 30 min prior to subcutaneous soman challenge, with no antimuscarink or oxime treatment, protected 60% of the animals against 2 × 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.