1. Preferential binding of the novel prostaglandin SC-46275 to canine gastric versus intestinal receptors.
- Author
-
Tsai BS, Keith RH, Perkins WE, Walsh RE, Anglin CP, Collins PW, Gasiecki AW, Bauer RF, Jones PH, and Gaginella TS
- Subjects
- Alprostadil metabolism, Alprostadil pharmacology, Animals, Anti-Ulcer Agents pharmacology, Cells, Cultured, Dogs, Female, Gastric Acid metabolism, Gastric Mucosa drug effects, Gastric Mucosa metabolism, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Intestine, Small drug effects, Intestine, Small metabolism, Male, Misoprostol metabolism, Misoprostol pharmacology, Muscle, Smooth metabolism, Muscle, Smooth ultrastructure, Radioligand Assay, Stomach drug effects, Tritium, Alprostadil analogs & derivatives, Anti-Ulcer Agents metabolism, Intestine, Small ultrastructure, Receptors, Prostaglandin E metabolism, Stomach ultrastructure
- Abstract
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.
- Published
- 1995