A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.
The gastric antisecretory effects of SC-29333, a novel prostglandin E1 analogs, were compared to the reference standard PGE1 methyl ester (PGE1ME) in gsstric fistula and Heidenhain pouch dogs. Secretion was stimulated submaximally by continuous intravenous infusion of either histamine or pentagastrin. Meal-stimulated gastric secretory studies were also conducted. SC-29333 effectively inhibited volume, acid output, and papsin secretion, in a dose-dependent manner. Intravenously (i.v.), SC-29333 was found to be approximately 30 times more potent than PGE1ME. The ranges of active i.v. bolus doses for SC-29333 and PGE1ME were 0.3-3.0 and 10-30 mug/kg, respectively. Unlike PGE1ME, SC-29333 was orally effective at doses of 10-30 mug/kg and was considerably better tolerated and longer acting than PGE1ME at active antisecretory doses. It is concluded, therefore, that SC-29333 is a potent, long-acting, orally effective inhibitor of gastric secretion in the dog.
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ABSTRACTNaturally occurring and synthetic prostaglandins acting at EP type receptors have a number of physiological actions, including cytoprotective and antisecretory effects, that are therapeutically useful. In addition they can produce other effects, such as diarrhea. It is possible that these actions are mediated by different EP receptor subtypes. The actions of a subtype-selective prostaglandin agonist has suggested that diarrhea i s not due to activity at the EP3 receptor, while cytoprotection and antisecretory actions may be. The recent development of a bioavailable EPI antagonist, SC-51089, has made it possible to examine this more directly. SC-30249, the active isomer of misoprostol, protects against indornethacin-induced gastric lesions and produces diarrhea in rats. SC-51089, ig, shifted the dose-response curve for SC-30249-induced diarrhea significantly to the right. ED,, values (assessed at 5 hr following administration of SC-30249) were 13.8 pg/kg (0.036 pmol/kg) for SC-30249 alone and 110.8 @kg (0.290 pmol/kg) for 5C-30249 plus SC-51089. This antagonism of diarrhea was overcome by higher doses of SC-30249. SC-30249 dosedependently inhibited gastric lesions induced by indomethacin (ED, , = 3.4 pgikg, 0.009 pmolikg, ig). SC-51089 did not reduce the cytoprotective effects of SC-30249 (ED, , = 1.1 Kg/kg, 0.003 pmol/ kg, ig, SC-30249 in combination with SC-51089). These results are consistent with the hypothesis that the EP1 receptor subtype mediates the diarrheagenic effect of FP receptor agonists, but not their cytoprotective actions. These results provide a mechanistic basis for cytoprotective prostaglandins with greatly reduced side effects. Q IYYS WiIey-Liss Inc
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