Acetylcholine receptors carbamylation

Mode of Action. All of the insecticidal carbamates are cholinergic, and poisoned insects and mammals exhibit violent convulsions and other neuromuscular disturbances. The insecticides are strong carbamylating inhibitors of acetylcholinesterase and may also have a direct action on the acetylcholine receptors because of their pronounced stmctural resemblance to acetylcholine. The overall mechanism for carbamate interaction with acetylcholinesterase is analogous to the normal three-step hydrolysis of acetylcholine however, is much slower than with the acetylated enzyme. 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

S-(-f)-Acetyl-j3-methylcholine (the euto-mer) is hydrolyzed by acetylcholinesterase at about half the rate of acetylcholine the R-(-)-enantiomer is a weak inhibitor of the enzyme (82). Work of Ringdahl (85) suggests that the markedly lower pharmacological activity of R-(-)-acetyl-j3-methylcholine is a result both of lower affinity for the muscarinic receptor(s) and lower intrinsic activity. The antipodes of carbamyl-jS-methylcholine (bethanechol) (34) displayed a eudismie ratio of 740 at rat jeju-... 

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