SC-46275 - A POTENT AND HIGHLY SELECTIVE AGONIST AT THE EP3 RECEPTOR

The agonist properties of SC-46275 have been investigated in EP recept or subtype-specific smooth muscle assays. In the isolated guinea pig v as deferens (GPVD), prostaglandin E2 (PGE2), via the EP3 receptor, pot ently inhibited electrically induced contractions with an EC50 of 5.4 +/- 1.1 nM. Sulprostone and misoprostol were both potent relaxers of t he GPVD yielding EC50s of 1.6 +/- 0.4 nM and 4.3 +/- 0.9 nM, respectiv ely, while butaprost (10 000 nM) was inactive. SC-46275 was by far the most potent agonist in the GPVD exhibiting an EC50 of 0.04 +/- 0.02 n M. PGE2, via the EP1 receptor, stimulates contractions in the longitud inal muscle layer of the guinea pig ileum (GPIL) with an EC50 of 74.4 +/- 10.6 nM. SC-46275 was extremely weak in this preparation, generati ng only 33% of the maximal PGE2 effect at 30 000 nM. The circular musc le layer of guinea pig ileum (GPIC) is responsive to inhibition of ele ctrically stimulated contractions by PGE, (EC50 = 179.6 +/- 20.8 nM) v ia the EP2 receptor. SC-46275 (up to 10 000 nM) was completely inactiv e in this preparation. We conclude from these findings that SC-46275 i s a very potent and highly selective EP3 receptor agonist. SC-46275 sh ould prove to be an extremely valuable tool in probing the physiologic al significance of EP3 receptors. The high potency of SC-46275 at the EP3 receptor may account for its antisecretory and cytoprotective acti ons, while its lack of activity at the EPI or EP2 sites may explain it s very weak diarrheagenic potential.