EP1 receptor antagonist blocks the diarrheagenic, but not cytoprotective, actions of a synthetic prostaglandin

Abstract

~~ ~~Strategy, Management dnd Health P d~y orrnu ation 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

Prostaglandin E2 inhibits renal collecting duct Na+ absorption by activating the EP1 receptor.

“…Low levels of EP 1 mRNA expression in stomach, adrenal, and brain may not reflect a lack of a functional significance in these tissues. EP 1 receptor expression may be limited to discrete but physiologically critical regions, including hypothalamus (14) and gastrointestinal muscularis mucosa (48) where EP 1 may play roles in fever and intestinal motility, respectively (15,49).…”

“…Importantly, at these concentrations, neither receptor antagonist acted as an agonist in rabbit collecting duct, producing no change in baseline [Ca ϩϩ ] i , or 22 Na ϩ flux. While these compounds show reasonable in vitro activity, their in vivo utility is limited by this low potency, low water solubility, and avid binding to plasma proteins (11,15). Thus, characterization of the in vivo effects of EP 1 antagonists on Na ϩ balance awaits the availability of improved EP 1 receptor antagonists.…”

“…Total RNA was purified from rabbit kidney and adrenal using TRIZOL-REAGENT™ (GIBCO BRL, Gaithersburg, MD) and reverse transcribed to singlestranded cDNA using SuperScriptII™ (reverse transcriptase and 0.5 g of oligo(dT) [12][13][14][15][16][17][18] according to manufacturer's protocol. The cDNAs were then amplified using EP 1 -selective primers.…”

“…The EP 1 receptor signals predominantly via increased cell Ca ϩϩ and phosphatidylinositol-bisphosphate hydrolysis (12)(13)(14). Several EP 1 receptor selective antagonists have been characterized, which may be used to block its functional activation (11,15). EP 2 and EP 4 receptors activate G s and cAMP generation (8,9,16).…”

QSAR rationales for the 1,2-diarylcyclopentenes as prostaglandin EP1 receptor antagonists: Potentially useful in the treatment of inflammatory pain

“…Studies which were aimed to identify key structural requirements to synthesize EP selective agonists and/or antagonists and to provide insights to the mechanism of receptor ligand selectivity revealed that sensitive positions for agonist-activity at the EP1 receptor is the hydroxyl group at the carbon 15 position and C-1 carboxylate [29]. The selective EP1 antagonists may aid in characterization of the effects mediated by this receptor subtype [30][31][32]. The reported selective EP1 receptor antagonists are the acylhydrazide derivative SC51322 (by Searle group) [31], ZD6416 (by AstraZeneca) [33,34], ONO-8713 (by Ono) [35] and thiophene derivative ((by Merck Frosst) [36].…”