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Vol. 59, Issue 6, 1446-1456, June 2001

Key Structural Features of Prostaglandin E2 and Prostanoid Analogs Involved in Binding and Activation of the Human EP1 Prostanoid Receptor

Mark D. Ungrin,1 Marie-Claude Carrière, Danielle Denis, Sonia Lamontagne, Nicole Sawyer, Rino Stocco, Nathalie Tremblay, Kathleen M. Metters, and Mark Abramovitz

Department of Biochemistry and Molecular Biology, Merck Frosst Center for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada

The structure-activity relationship (SAR) of prostaglandin (PG) E2 at the human EP1 prostanoid receptor (designated hEP1) was examined via the binding and activation of this receptor by a series of 55 prostanoids and analogs. Using clonal human embryonic kidney 293 cell lines expressing recombinant hEP1, affinity (Ki), potency (EC50), and efficacy data were obtained using a radioligand competitive binding assay and an aequorin-based calcium functional assay. All compounds behaved as full agonists (90-100% of the response elicited by PGE2) in this assay, and the correlation between the Ki and EC50 values was highly significant (R2 = 0.86). The results from the SAR analysis can be summarized as follows: 1) the existence and configuration of hydroxyl groups at the 11 and 15 positions of PGE2 and prostanoid analog structures play a critical role in agonist activity; 2) the carboxyl group is also important for activity and modification of the carboxylic acid to various esters results in greatly reduced affinity and potency; 3) the activity of structures with moderate or weak potency can be enhanced by modification of the omega -tail; and 4) modifications to the ketone at the 9-position are better tolerated, with 9-deoxy-9-methylene-PGE2 being the most potent agonist tested in the functional assay. The impact of other modifications on agonist potency is also discussed. The results from this study have identified, for the first time, the key structural features of PGE2 and related prostanoids and prostanoid analogs necessary for activation of hEP1.

1 Current address: Department of Medical Biophysics, University of Toronto, 610 University Ave., Toronto, Ontario, M5G 2M9 Canada.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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