Somatostatin depleting potency of cysteamine-related thiols and amines in the rat: structure-activity relation
Szabo, S.; Reichlin, S.; Bollinger-Gruber, J.A.; Brown, A.
Journal of Pharmacology and Experimental Therapeutics 263(2): 752-756
1992
ISSN/ISBN: 0022-3565 PMID: 1359114 Document Number: 390791
Cysteaqmine, 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 neucleophilic and reducing potencies. Adult female rats were sacrified 4 hr after p.o. administration of the test chemical 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-propaneditthiol (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 lt .01) with electron affinity of -SH, -NH-2, -OH and -CN radicals in terminal alkyl chemicals. The structural requirement for decreasing activity is the presence of either -SH and -NH-2 on a 2 to 3 carbon alkyl or aryl molecule. Both radicals when present together increase potency. Replacement of the potent nucleophilic-SH with less reactive-OH in a linear or cyclic molecule decreases, whereas insertion of a carboxyl group next to amine in cysteamine (i.e., cysteine) abolishes both IRS decreasing and duodenal ulcerogenic potencies. IRS decreasing activity is a unique property of cysteamine and its close alkyl and aryl analogs.