Reversible and irreversible inhibitory activity of succinic and maleic acid derivatives on acetylcholinesterase.
Aryl succinic and maleic acid derivatives are potent inhibitors of bovine acetylcholinesterase in vitro. Succinic acid aminophenol derivatives 1b-e and 2b-d act as reversible inhibitors of acetylcholinesterase, while maleic acid aminophenol derivatives 3b-d and 4c-e act as choline subsite-directed irreversible inhibitors, detected by dialysis in the presence of edrophonium. Linear relationships between the logarithm of the velocity of hydrolysis of acetylcholine plotted against the time of incubation at several different inhibitor concentrations were determined. The K(i) for reversible competitive inhibitors was determined. For irreversible inhibitors the K(i) for the dissociation constant of the enzyme-inhibitor complex at the beginning of the recognition process was also determined as well as the inactivation constant of the enzyme-inhibitor adduct formation k(+2) and the bimolecular inhibition constant k(i) for the inhibition of acetylcholinesterase by aminophenol derivatives 3b-d and 4c-e. The conclusions of this study can be summarized as follows for both families: (a) the aromatic moiety played a critical role in the recognition of the active site; (b) in case of the reversible inhibitor, when the ester function took the place of the hydroxyl fragment, there was an important increase in the affinity; and (c) the distance between phenolic hydroxyl and nitrogen was critical because the inhibition is ortho<<meta<para.
Trujillo-Ferrara
J
J
Sección de Graduados y Departamento de Bioquímica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, México D.F. 11340, Mexico. jtrujillo@ipn.mx
Vázquez
Iván
I
Espinosa
Judith
J
Santillan
Rosa
R
Farfán
Norberto
N
Höpfl
Herbert
H
D000110:Acetylcholinesterase / Q000378:metabolism*; D000627:Aminophenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008298:Maleates / Q000494:pharmacology*; D008968:Molecular Conformation; D015394:Molecular Structure; D011522:Protons; D019802:Succinic Acid / Q000494:pharmacology*; D013997:Time Factors
D000627:Aminophenols; D002800:Cholinesterase Inhibitors; D008298:Maleates; D011522:Protons; C030272:maleic acid; D019802:Succinic Acid; D000110:Acetylcholinesterase