N alpha-dansyl-L-arginine 4-phenylpiperidine amide. A potent and selective inhibitor of horse serum cholinesterase

The relationship between chemical modifications of arginine derivatives and inhibitory activity to horse serum cholinesterase (BuChE) was investigated. It provided a new insight into the topography of the active site of BuChE. 1) BuChE has the hydrophobic binding pocket, the depth of which correspon...

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Bibliographic Details
Published in:The Journal of biological chemistry 1988-08, Vol.263 (23), p.11269-11273
Main Authors: Hijikata-Okunomiya, A, Okamoto, S, Tamao, Y, Kikumoto, R
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Arginine - analogs & derivatives
Arginine - pharmacology
Biological and medical sciences
Cholinesterase Inhibitors - pharmacology
Cholinesterases - blood
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Horses
Hydrolases
Kinetics
Spectrometry, Fluorescence
Structure-Activity Relationship
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Summary:The relationship between chemical modifications of arginine derivatives and inhibitory activity to horse serum cholinesterase (BuChE) was investigated. It provided a new insight into the topography of the active site of BuChE. 1) BuChE has the hydrophobic binding pocket, the depth of which corresponds to the length of ethylpiperidine. 2) In the opposite side to the hydrophobic binding pocket, BuChE has a certain entity which repulses carboxyl group at the 2-position of piperidine of L-arginine piperidine amide. 3) The P site of BuChE can allow 4-propyl and 4-phenyl group attached to piperidine. Comparison of the results with those of thrombin and trypsin clearly revealed similarities and dissimilarities among BuChE, trypsin, and thrombin in the active site topography, and hence, we introduce a new selective inhibitor for BuChE, N alpha-dansyl-L-arginine 4-phenylpiperidine amide. It inhibits BuChE strongly (Ki = 0.016 microM), whereas it inhibits trypsin, thrombin, plasmin, and glandular kallikrein only weakly and shows actually no inhibition on acetylcholinesterase from the human erythrocyte. In addition, the new inhibitor becomes highly fluorescent when bound with BuChE, indicating that the compound is an ideal probe of the interactions of BuChE as well as a titrant of it.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(18)37952-3