Anti-AChE activity

Based on the anti-AChE activity of huperzine B (HB, 47), a natural homolo-gue of HA, Rajendran et al. prepared 48a-c, hybrid analogs of HA and HB. " In comparison with ( )-HA, 48a-c are approximately 10-100 times less active in AChE inhibition. 

Oxidation. Any and all biotransformations of carbamate insecticides result in their loss of anti-AChE activity. Oxidation is the most important metabolic fate of the carbamates and cytochrome P-450 is the most important catalyst. One or more isoenzymes of cytochrome P-450 can oxidize a carbamate molecule in many different places, depending on its structure. In Figure 2, arrows indicate places susceptible to oxidation in selected carbamate molecules. 

Fig. 4 presents the dependence of log k, and selectivity for NTE, log [ (NTE)/ i(AChE)], on the hydrophobicity (In. 7tCH2=0.5) of the R groups for the different compounds I-IV. The differential effect of changing the hydrophobicity on the anti-NTE and anti-AChE activities observed for four OP series suggests differences in the structure and inhibitory specificities of the active sites of the two target esterases [58,59], The calculated from the bimolecular inhibitor constants values of RIP = i(NTE)/ i(AChE) are presented in Table 1. 

Other agents useful as cholinesterase reactivators include nicotinhydroxamic acid methoiodide and the bis-compound obidoxime (not available in the United States). Toxic overdoses of carbamate AChE inhibitors are not reversible with pralidoxime-type antidotes.13 In fact, because of some anti-AChE activity of their own, they would actually aggravate the toxicity of physostigmine and neostigmine overdoses. 

TABLE 1. Anti-AChe activity of aryl N-methylcarbamates on... 

Table 2. Anti-AChE activity of N-aryl oxadiazolones on susceptible(S) and resistant(R) Nephotettix cincticeps...

Physostigmine (Fig. 16.9) was discovered in 1864 and its stmcture was established in 1925. It is extracted from the plant Physostigma venenosum (calabar bean) and it was the first compound found to show anti-AChE activity. Physostigmine has serious side effects which limit its use, but it provided a prototype which medicinal chemists could use as a lead compound and improve it. The important stmc-tural elements within the molecule are shown in Figme 16.9. 

Organophosphate and carbamate pesticides are potent inhibitors of the enzyme cholinesterase. The inhibition of cholinesterase activity by the pesticide leads to the formation of stable covalent intermediates such as phosphoryl-enzyme complexes, which makes the hydrolysis of the substrate very slow. Both organophosphorus and carbamate pesticides can react with AChE in the same manner because the acetylation of the serine residue at the catalytic center is analogous to phosphorylation and carbamylation. Carbamated enzyme can restore its catalytic activity more rapidly than phosphorylated enzyme [17,42], Kok and Hasirci [43] reported that the total anti-cholinesterase activity of binary pesticide mixtures was lower than the sum of the individual inhibition values. 

Compound 10 was evaluated for anti-bacterial activity and acetylchohnesterase (AChE) inhibitory activities. This compound was foimd to be inactive in antibacterial assay and exhibited AChE inhibitory activity with an ICj, value of 67 pM. Acetylcholine serves as a neurotransmitter in the central and peripheral nervous system. Acetylcholinesterase (AChE) stops the function of acetylcholine by its... 

Figure 4-3. IC50 ( jM) of anti-ChE activities of HA derivatives on AChE (rat erythroc3fte membrane) and BuChE (rat serum) over a concentration range from 1 nM to 10 nM. Data from Refs. 121 and 122.

ORNL assigned a factor of 10 for the nncertainty factor for the extrapolation of data from animals to humans (UFa) becanse no evidence suggests that humans are less susceptible than rats to GD. ORNL cited the evidence that rodents have much lower RBC-AChE activity than humans (EUin 1981), suggesting that rats might be more susceptible than hnmans to anti-ChE compounds, but also noted that the lower RBC-AChE... 

The OP insecticides, as discussed elsewhere in this book, have as a primary mechanism of acute toxicity the inhibition of the critical and widespread nervous system enzyme AChE. However, the anticholinesterase (anti-ChE) potencies do not correspond with the acute toxicity levels (Chambers et a ., 1990), indicating that metabolism is an important factor in determining the overall toxicity level. The OP insecticides evolved from the chemical technologies of World War II, which were used to develop the anti-ChE nerve agents. The OP inseeticidc.s bear some chemical resemblance to these nerve agents but are generally less toxic, often require metabolic activation to display anti-ChE activity and therefore are slower to act, and usually have more complex chemical substituents. 

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