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|Title:||The Synthesis of O-Alkylhydroxylamines and the Potentiation of Histamine in Canine Colonic Tissue|
|Advisor:||Bell, Russell A.|
Rangachari, P. K.
|Keywords:||synthesis, potentiation, histamine, canine, colonic, tissue, compounds, enzyme|
|Abstract:||<p> Treatment of canine colonic tissue with some O-alkyl and O-benzyl hydroxylamines potentiated the response of the tissue to histamine in different experimental environments.</p> <p> Sixteen O-substituted hydroxylamine compounds were synthesized using a modification of the Gabriel synthesis. These compounds were tested for their ability to potentiate histamine in canine colonic tissue through diamine oxidase inhibition.</p> <p> Three procedures were used to determine their activity: (1) secondary rise -hydroxylamine derivatives were added to epithelial tissue preparations in Ussing chambers after an initial dose of histamine. Active compounds caused a secondary increase in the short circuit current across the tissue, (2) dose-response profiles were constructed for several hydroxylamine compounds to determine whether they caused a significant shift to the left of the normal histamine curve (potentiated response), and (3) diamine oxidase enzyme assays were performed to examine the ability of the hydroxylamine derivatives to inhibit partially purified diamine oxidase. This aided in determining if inactive compounds could not potentiate histamine due to an inability to access the enzyme in the epithelial preparation.</p> <p> The structure-activity relation observed indicates that: (1) active compounds are oxygen and not nitrogen substituted hydroxylamines, (2) branched compounds are less active than their straight chain analogues, (3) greater steric bulk of the alkyl substituent can decrease the activity of the compound, (4) the presence of a carbon-carbon double (allyl) or triple (4-pentynyl) bond does not affect the activity of the compound, (5) longer straight chain O-alkyl hydroxylamines are less active than shorter chain derivatives, (6) steric bulk of the benzyl compounds is not likely to be the cause of its inability to inhibit diamine oxidase since the cinnamyl derivative is active, and (7) meta- and para-oxygen substituents (-OH, -OCH3) on O-benzyl hydroxylamines increase their diamine oxidase inhibiting properties.</p>|
|Appears in Collections:||Open Access Dissertations and Theses|
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