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Research ArticleArticle

Probing the “Active Site” of Diamine Oxidase: Structure-Activity Relations for Histamine Potentiation byO-Alkylhydroxylamines on Colonic Epithelium

A. High, T. Prior, R. A. Bell and P. K. Rangachari
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 490-501;
A. High
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T. Prior
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R. A. Bell
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P. K. Rangachari
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Abstract

The responses of the canine colonic epithelium to histamine are potentiated by O-alkylhydroxylamines. A study of a series of such compounds suggested that active compounds had the structure R-O-NH2, substitution of a nitrogen led to total loss of activity. The locus of the potentiation effect was traced to the inhibition of diamine oxidase. A new series of aliphatic and aromatic O-alkylhydroxylamines were synthesized to explore further the structure-activity relations of this effect. The potentiating effects of these compounds were determined by examining the changes in short circuit current (Isc) produced by histamine and from the activity of a soluble preparation of diamine oxidase. We found that 1) branched compounds are less active than their straight chain counterparts, 2) greater steric bulk of the aliphatic substituent decreased activity, 3) the presence of a double bond had no significant effect though a triple bond reduced activity, 4) longer straight chain compounds were less active than the shorter chain derivatives and 5) all benzylic compounds were less active than the straight chain aliphatics. O-1-benzyl was inactive however the meta or para oxygen substituted compounds as well as theO-(1-E-Cinnamyl) derivative were active. A current model for the action of diamine oxidase proposes a crucial role for a trihydroxyphenylalanine quinone cofactor as part of the active site together with a copper atom. Using molecular modeling based on our inhibition data we are able to define the region of space that is just beyond the reactive carbonyl of the trihydroxyphenylalanine residue at the active site of diamine oxidase. We suggest that a negatively charged species, such as an aspartate or a glutamate, resides in a trough about 7 to 8 Å from the trihydroxyphenylalanine carbonyl carbon and this species aids in the strong selective binding of substrates such as putrescine and histamine.

Footnotes

  • Send reprint requests to: Dr. P. K. Rangachari, McMaster University, HSC-3N5C, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

  • ↵1 This work was supported by an operating grant to P.K.R. and R.A.B. from the Medical Research Council of Canada.

  • Abbreviations:
    ACN
    acetonitrile
    DAO
    diamine oxidase
    DMF
    N,N dimethylformamide
    DMSO
    dimethylsulfoxide
    FID
    free-induction decay
    Isc
    short-circuit current
    NMR
    nuclear magnetic resonance
    TMS
    tetramethylsilane
    TOPA
    trihydroxyphenylalanine
    • Received October 24, 1997.
    • Accepted July 20, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Probing the “Active Site” of Diamine Oxidase: Structure-Activity Relations for Histamine Potentiation byO-Alkylhydroxylamines on Colonic Epithelium

A. High, T. Prior, R. A. Bell and P. K. Rangachari
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 490-501;

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Research ArticleArticle

Probing the “Active Site” of Diamine Oxidase: Structure-Activity Relations for Histamine Potentiation byO-Alkylhydroxylamines on Colonic Epithelium

A. High, T. Prior, R. A. Bell and P. K. Rangachari
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 490-501;
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