The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Abstract

Controlled inhibition of brain acetyl-and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k i ) and decarbamylation (k r ) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k i was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k i depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

“…In Figure 5 we can see that the retrodonor process is due to the C3, C4, C6, C8, O12, and N30 atoms for regions ( − ) (Figure 5(a)) and C2, C3, C5, C6, C7, C8, and N30 atoms for regions ( + ) (Figure 5(b)) for the more active molecule 5 that causes one electronic donation capacity quantified by the electrophilicity index (see Table 7) which allows the stabilization in the active site and postulate the retrodonor process by the C3, C6, C8, and CN30 ( Figure 5(a)) atoms. However the molecular set studied is hybrid molecules that act as MAO-B inhibitors by virtue of the covalent bond formed by the propargylamino moiety with the Flavin Adenine Dinucleotide (FAD) cofactor and as ChE inhibitors by interaction at the catalytic site with the N-benzyl-cycloalkylamino moiety and at the peripheral site (PAS of AChE) with the heteroaromatic moiety [13,[75][76][77][78][79][80][81]. Therefore, retrodonation on the central ring might even take place but as an additional interaction.…”

Phenolic profiling and therapeutic potential of local flora of Azad Kashmir; In vitro enzyme inhibition and antioxidant

“…Specific inhibitors interact with enzymes and block their activity towards their corresponding physiological substrates. The importance of enzyme inhibitors as drugs is enormous, since these molecules have been used for treating a large number of physiological conditions [30]. Acetyl cholinesterase plays a vital role in the central and peripheral nervous systems.…”

Evento de Intoxicación en Perros de Zona Urbana mediante Cebos Contaminados con Aldicarb

“…En el diagnóstico, porque la actividad de la butirilcolinesterasa/ colinesterasa plasmática (BChE) refleja la actividad de la acetilcolinesterasa del Sistema Nervioso Central (SNC), responsable de la presentación de los signos (Groner et al, 2007) En la práctica veterinaria, el agente causal no es usualmente identificado dada la carencia de equipos de cromatografía líquida o gaseosa en los laboratorios veterinarios, lo cual dificulta las denuncias y registros oficiales de envenenamiento. El uso de técnicas de laboratorio para la medición de BChE y la cromatografía en capa fina son métodos factibles y de fácil acceso para su uso en medicina veterinaria.…”