RT Journal Article
SR Electronic
T1 Key Structural Features of Prostaglandin E<sub>2</sub> and Prostanoid Analogs Involved in Binding and Activation of the Human EP<sub>1</sub> Prostanoid Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1446
OP 1456
DO 10.1124/mol.59.6.1446
VO 59
IS 6
A1 Mark D. Ungrin
A1 Marie-Claude Carrière
A1 Danielle Denis
A1 Sonia Lamontagne
A1 Nicole Sawyer
A1 Rino Stocco
A1 Nathalie Tremblay
A1 Kathleen M. Metters
A1 Mark Abramovitz
YR 2001
UL http://molpharm.aspetjournals.org/content/59/6/1446.abstract
AB 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 (K i), 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 K i 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 ω-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.