Preferential binding of the novel prostaglandin SC-46275 to canine gastric versus intestinal receptors.
Prostaglandins (PGs) in the E-series exhibit potent gastric antisecretory activity, but can also cause diarrhea, which is mediated via PGE receptors. SC-46275, an omega-chain cyclopentenyl analog of the E-type PG enisoprost, was evaluated with other E-PGs for PGE receptor binding activity in gastric and intestinal tissues. SC-46275, enisoprost, misoprostol and PGE1 were first evaluated in enriched canine gastric parietal cells with [3H]misoprostol free acid binding and subsequently with [3H]PGE1 binding in canine intestinal tissues where misoprostol free acid had weak receptor binding activity. The receptor binding potency of SC-46275 (IC50, 0.013 mM) in enriched canine parietal cell preparations was found to be much greater than misoprostol and enisoprost (IC50, 10 and 8 nM), whereas PGE1 had the least potency (IC50, 37 nM). Similar relative potencies for these PGs were also obtained in the inhibition of histamine-stimulated acid secretion in enriched parietal cell preparations. In small intestinal mucosal and muscle membranes, the receptor binding potency of SC-46275 (IC50, 13 and 20 microM) was much less than misoprostol or enisoprost (IC50, 0.39-1.2 microM) and substantially less than PGE1 (IC50, 0.017 and 0.066 microM). This weak binding activity of SC-46275 in intestinal tissues is consistent with its reported weak diarrheagenic activity in the rat. These results suggest that SC-46275 binds preferentially to gastric vs. intestinal PGE receptors and is specific for the EP3 receptors.
Tsai
B S
BS
Department of Immunoinflammatory Diseases Research, Searle Research and Development, Skokie, Illinois, USA.
Keith
R H
RH
Perkins
W E
WE
Walsh
R E
RE
Anglin
C P
CP
Collins
P W
PW
Gasiecki
A W
AW
Bauer
R F
RF
Jones
P H
PH
Gaginella
T S
TS
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure*; D008297:Male; D016595:Misoprostol / Q000378:metabolism / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism / Q000648:ultrastructure; D011869:Radioligand Assay; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D013270:Stomach / Q000187:drug effects / Q000648:ultrastructure*; D014316:Tritium
D000897:Anti-Ulcer Agents; D018078:Receptors, Prostaglandin E; D016595:Misoprostol; D014316:Tritium; C072122:SC-46275; D000527:Alprostadil; C054594:enisoprost