3-Carbamyl-N-allylquinuclidinium bromide. Effects on cholinergic activity and protection against soman.
3-Carbamyl-N-allylquinuclidinium bromide (CAB) was synthesized and evaluated for its pharmacological effects on cholinergic activity and for protection in vivo against soman toxicity in guinea pigs. This carbamylated derivative of N-allyl-3-quinuclidinol (NAQ), a potent inhibitor of high-affinity choline uptake, demonstrated stereospecific alterations of cholinergic function as well as protection against soman. The R-isomer, but not the S-isomer, of CAB inhibited erythrocyte acetylcholinesterase (AChE) and plasma pseudocholinesterase (pChE) in a concentration-response manner (IC50 = 25 and 29 microM, respectively). The R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake (IC50 = 4.8 microM) than S-CAB (IC50 = 63 microM). When R-CAB (10 mumol/kg, i.m.) was administered to guinea pigs 30 min prior to soman in conjunction with atropine (16 mg/kg, i.m.) given 1 min post-soman, the compound significantly reduced lethality up to 5 LD50S. This represents enhanced protection when compared to NAQ (up to 100 mumol/kg); the S-isomer of CAB failed to protect against soman intoxication. The results demonstrate that reversible inhibition of AChE with suppression of acetylcholine synthesis into a single compound, CAB, enhances the protection against organophosphates.
Sterling
G H
GH
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140.
Doukas
P H
PH
Jackson
C
C
Caccese
R
R
O'Neill
K J
KJ
O'Neill
J J
JJ
D000109:Acetylcholine / Q000096:biosynthesis; D000110:Acetylcholinesterase / Q000097:blood; D000498:Allyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002794:Choline / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D010276:Parasympatholytics / Q000494:pharmacology*; D011812:Quinuclidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012999:Soman / Q000633:toxicity*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism
D000498:Allyl Compounds; D002800:Cholinesterase Inhibitors; D010276:Parasympatholytics; D011812:Quinuclidines; C079660:N-allyl-3-quinuclidinol; C079661:3-carbamyl-N-allylquinuclidinium; D012999:Soman; D000110:Acetylcholinesterase; D002794:Choline; D000109:Acetylcholine