BuChE inhibitors

Most N-methyl and N,N-dimethyl carbamates are better AChE inhibitors than BuChE inhibitors. 

As mentioned above, galantamine has two basic mechanisms of action. It reversibly inhibits cholinesterases, being approximately 50-fold more potent as an AChE inhibitor than a BuChE inhibitor. It also interacts directly with nAChRs, potentiating their activation by subsaturating concentrations of classical agonists (Pereira et al., 2002). 

FIG. 9. In I itro determination of total ChE activity described as (A) butyrylthiocholine (BTC) and (B) acetylthiocholiirc (ATC) hydrolysis rates in tissues following iso-OMPA (BuChE inhibitor) or BW284C5 (AChE inhibitor) incubalLon (15 min) with brain, plasma, and saliva samples obtained from naive adult male rats. The data represent the mean SD for three deicrminations-Adapted from Kousba el til. (2003),... 

In the protocol of Fcaster el ui (2004), three substrates are used ATCh, BTCh, and PTCh. The cholinesterase activities in whole blood are measured separately with each substrate, and the activities of AChE and BuChE are calculated by using the so-called sensitivity coefficients. These are determined prior to the assay by applying selective AChE and BuChE inhibitors to reference samples in order to evaluate the contribution of each enzyme to the hydrolysis of each of the three substrates. 

Mean SD activity expressed as prniol min mg Hb. Activities measured in the presence of 0.2 mW quinidinc, a selective BuChE inhibitor. 

Fent, K. and Bucheli, T.D. (1994). Inhibitors of hepatic microsomal monooxygenase system by organotins in vitro in freshwater fish. Aquatic Toxicology 28, 107-126. 

In this scheme, EOH is the enzyme, IX is the inhibitor (either a carbamate or an organophosphate). EOH(IX) is analogous to the Michaelis Menton comploc seen with the substrate reaction. EOI is the acyl-enzyme intermediate for carbamates or a phosphoro-enzyme intermediate for the organophosphates. The equilibrium constant for this reaction (K ) is defined as k /k and the phosphorylation or carbamylation constant is defined as k2- In this study 42)y ANTX-A(S) was found to be more specific for AChE than BUChE. The double reciprocal and Dixon plot of the inhibition of electric eel AChE indicated that the toxin is a non-competitive inhibitor decreases, k remains unchanged) (Figure 2). 

Fig. 11.3. Comparative properties of secreted and somatic (i.e. neuronal) AChEs of N. brasiliensis. The properties of the three secreted AChEs are broadly similar, and this figure represents the net activity of a mixture of these enzymes. The top panels depict substrate specificities, and show activity against acetyl-thiocholine (open circles) and butyrylthiocholine (solid circles) over a range of substrate concentrations [S] between 0.05 and 20 mM (log scale). The bottom panels show sensitivity to the AChE-specific inhibitor BW284c51 (solid triangles) and the BuChE-specific inhibitor iso-OMPA (open triangles) over a range of inhibitor concentrations [I] between 10-9 and 10-3 M (log scale).

Some quinoline alkaloids from the aerial parts of Skimmia laureola (DC.) Dene have shown antiChE activity in vitro and methyl isoplatydesmine (49) was shown to be the most active inhibitor of both AChE and BuChE. Solanidine (50), related compounds and glycosides are... 

FIGURE 12—24. Icon for the cholinesterase inhibitor donepezil. This is the current first-line treatment for Alzheimer s disease, since it is a once daily agent without significant hepatotoxicity. It is a reversible agent, selective for acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE), developed by American and Japanese companies. 

FIGURE 12-25. Icon for the cholinesterase inhibitor tacrine. This was the first cholinesterase inhibitor, but since it is a hepatoxotin, it has been relegated to second-line use. Also, it must be given four times daily, is difficult to dose, and has several drug interactions. It is short-acting, reversible, and nonselective, inhibiting both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). 

Arisugacin not only demonstrates impressive potency in inhibiting AChE with an IC50 value of 1 nM, but more importantly, it is highly selective for AChE since >18 flM is required to inhibit butyrylcholinesterase [BuChE], In contrast, tacrine and other inhibitors are less selective for AChE. In the case of tacrine, it is actually more selective for BuChE with an IC50 value of 12 nM, thereby raising concerns about its potential in liver damage.13... 

Donepezil HC1, a piperidine, is a highly selective inhibitor of the enzyme AChE [3,4] that is chemically unique from other AChE inhibitors [5, 6]. In vitro and preclinical studies have demonstrated that donepezil is approximately 1200 times more selective for AChE in the brain than for butyrylcholinesterase (BuChE) in the periphery [3, 4, 7]. Phase II and III studies conducted in the United States have shown that donepezil (5 or 10 mg once daily) produces statistically significant improvements in cognition and global function in patients with AD [8-10]. Its clinical efficacy and minimal side-effect profile are thought to be related to its specific inhibition of AChE in the areas of the brain affected by the cholinergic deficit that typifies this disease [3, 4, 7],... 

Compared with AChE in animals such as horse and rat, HA is a weaker inhibitor of human serum BuChE. This selectivity for AChE as opposed to BuChE (similar to that of galanthamine) may suggest a better side-effects profile. However, a stronger inhibition of BuChE could be important in the later stage of AD and could offer more protection over amyloid p-peptide (Ap) plaque deposition. In contrast to isoflurophate, the AChE activity did not decrease with the prolongation of incubation with HA in vitro, and the AChE activity returned to 94% of the control after being washed five times, which indicates a reversible inhibitory action. ... 

Substrate preferences for AChEs and BuChEs vary with the species. Both mammal and bird AChEs rapidly hydrolyze ACh and its thiocholine analog acetylthiocholine (AcTh) (Silver 1974). Plasma-BuChE activity in the rat is reported to favor propionyl rather than butyryl substrates (Augustinsson 1948 Hoffmann et al. 1989). AChEs and BuChEs respond differently to increasing substrate concentration. AChEs are inhibited by excess substrate above 1-2 millimolars (mM) (Wilson et al. 1997 Silver 1974). BuChEs are less sensitive. BuChEs are preferentially inhibited by the selective inhibitor iso-OMPA and quinidine, and AChEs by the bisquatemary compound BW284c51. 

Paraoxon, sarin, and soman inhibit AChE, BuChE, and CarbE almost to the same extent. DFP inhibits BuChE and CarbE to the same extent and 1,000-fold more than AChE. Diphenyl -nitrophenyl phosphinate inhibits CarbEs more than 1,000-fold that of the ChEs. This explains why bis-p-nitrophenylphosphate is a specific inhibitor of CarbEs. A problem for CarbE as a scavenger is that VX is a 10,000-fold better inhibitor of the ChEs, and that ecothiophate is... 

The reaction of an OP with AChE, BuChE, or other B-esterases is similar to the reaction of AChE with ACh, except that the hydrolysis step is much slower or, in some cases, may not occur at all. Its basis is a phosphorylation of the enzyme via a nucleophilic attack. The electronegative serine hydroxyl at the catalytic site reacts with the electropositive phosphorus atom of the inhibitor to form an OP-ChE complex and loss of a side group on the phosphorus atom, known as the leaving group (X). The phosphorylated enzyme may, in time, reactivate by... 

A novel series of tacrine-selegiline hybrids for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B) have also been synthesized [181]. 

---