Tsai B S, Keith R H, Perkins W E, Walsh R E, Anglin C P, Collins P W, Gasiecki A W, Bauer R F, Jones P H, Gaginella T S
Department of Immunoinflammatory Diseases Research, Searle Research and Development, Skokie, Illinois, USA.
J Pharmacol Exp Ther. 1995 Oct;275(1):368-73.
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.
E系列前列腺素（PGs）具有强大的胃抗分泌活性，但也会引起腹泻，这是通过前列腺素E（PGE）受体介导的。SC-46275是E型PG依尼前列素的ω链环戊烯基类似物，与其他E-PGs一起在胃和肠组织中评估了其与PGE受体的结合活性。首先在富含犬胃壁细胞中用[3H]米索前列醇游离酸结合法评估SC-46275、依尼前列素、米索前列醇和PGE1，随后在米索前列醇游离酸受体结合活性较弱的犬肠组织中用[3H]PGE1结合法进行评估。发现在富含犬壁细胞制剂中，SC-46275（IC50，0.013 mM）的受体结合能力远大于米索前列醇和依尼前列素（IC50，10和8 nM），而PGE1的能力最弱（IC50，37 nM）。在富含壁细胞制剂中抑制组胺刺激的胃酸分泌时，这些PGs也获得了类似的相对效力。在小肠黏膜和肌膜中，SC-46275（IC50，13和20 μM）的受体结合能力远小于米索前列醇或依尼前列素（IC50，0.39 - 1.2 μM），且远小于PGE1（IC50，0.017和0.066 μM）。SC-46275在肠组织中的这种弱结合活性与其在大鼠中报道的弱致泻活性一致。这些结果表明，SC-46275优先与胃而非肠PGE受体结合，并且对EP3受体具有特异性。
