3-carbamyl-N-allylquinuclidinium bromide: Effects on cholinergic activity and protection against soman

Abstract

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 ( ic 50 = 25 and 29 μM, respectively). The t R-isomer of CAB was also a more potent inhibitor of high-affinity choline uptake ( ic 50 = 4.8 μM) than S-CAB ic 50 = 63 μM). When IRR-CAB (10 μmol 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 postsoman, the compound significantly reduced lethality up to 5 ld 50s. This represents enhanced protection when compared to NAQ (up to 100 μmol 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.