Somatostatin depleting potency of cysteamine-related thiols and amines in the rat: structure-activity relation.
Cysteamine, a potent duodenal ulcerogen, stimulates gastric acid and gastrin secretion and decreases immunoreactive somatostatin (IRS) from the gut and hypothalamus of the rat. To elucidate the structural requirements for this effect, we tested a series of cysteamine analogs for their IRS decreasing activity in comparison with their nucleophilic and reducing potencies. Adult female rats were sacrificed 4 hr after p.o. administration of the test chemicals given in molar equivalents to 30 mg/100 g of cysteamine-HCl. IRS decreasing activity in gastric mucosa, expressed as percentage of controls is listed in descending order: cystamine (55%), cysteamine (59%), 2-dimethylaminethanethiol (59%), ethylamine (66%), 1,3-propanedithiol (70%), propylamine (75%) and 3-aminothiophenol (79%). The following thiols and amines had no IRS decreasing effect (80% of controls): L-cysteine, ethanethiol, 1-propanethiol, penicillamine, dimercaprol, 1-4-dithiothreitol, ethanolamine, propionitrile, n-butyronitrile, o-, m- or p-aminophenol. The aryl 2-, 3- or 4-aminothiophenols, unlike most of their aminophenol analogs also decreased immunoreactive prolactin in the pituitary by 38 to 78%. IRS decreasing activity was independent of the reducing potency of cysteamine derivatives but was correlated significantly (r = 0.793, P < .01) with electron affinity of -SH, -NH2, -OH and -CN radicals in terminal alkyl chemicals. The structural requirement for decreasing activity is the presence of either -SH and -NH2 on a 2 to 3 carbon alkyl or aryl molecule. Both radicals when present together increase potency.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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Szabo
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Reichlin
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Bollinger-Gruber
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Brown
D000588:Amines / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D003538:Cystamine / Q000494:pharmacology; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D005021:Ethylamines / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000588:Amines; D000814:Aniline Compounds; D005021:Ethylamines; D011437:Propylamines; D013438:Sulfhydryl Compounds; D013004:Somatostatin; D003543:Cysteamine; D003538:Cystamine; C041564:ethylamine