Potent EP Research Articles

Difluoromethylene at the γ-Lactam α-Position Improves 11-Deoxy-8-aza-PGE1 Series EP4 Receptor Binding and Activity: 11-Deoxy-10,10-difluoro-8-aza-PGE1 Analog (KMN-159) as a Potent EP4 Agonist.

A series of small-molecule full agonists of the prostaglandin E2 type 4 (EP4) receptor have been generated and evaluated for binding affinity and cellular potency. KMN-80 and its gem-difluoro analog KMN-159 possess high selectivity relative to other prostanoid receptors. Difluoro substitution is positioned alpha to the lactam ring carbonyl and results in KMN-159's fivefold increase in potency versus KMN-80. The two analogs exhibit electronic and conformational variations, including altered nitrogen hybridization and lactam ring puckering, that may drive the observed difluoro-associated increased potency within this four-compound series.

Vasoconstriction induced by activation of EP 1 and EP 3 receptors in human lung: effects of ONO-AE-248, ONO-DI-004, ONO-8711 or ONO-8713

This study investigated the effects and selectivity of ONO-AE-248, ONO-DI-004, ONO-8711 and ONO-8713 on EP 1 and EP 3 receptors in human pulmonary vessels. The prostanoid receptors involved in the vasoconstriction of human pulmonary arteries (HPA) are TP and EP 3 whereas in pulmonary veins (HPV), this response is associated with TP and EP 1. The experiments were performed in presence of BAY u3405 (TP antagonist). ONO-DI-004 (EP 1 agonist) and ONO-AE-248 (EP 3 agonist), exhibited little or no activity in HPV whereas contractions were induced in HPA with ONO-AE-248. In HPV, the contractions produced with sulprostone (EP 1,3 agonist) were blocked in a non competitive manner by both EP 1 antagonists (ONO-8711, 30 μM; ONO-8713, 10 μM). The involvement of EP 1 mediated contraction in HPV was also observed during the vasorelaxations induced with PGE 1 and 5- cis-carba-PGI 2. In pre-contracted HPV treated with AH6809 (30 μM; EP 1 antagonist) the PGE 1 vasorelaxations were potentiated, while unchanged in HPA. These results demonstrate the selectivity of ONO-AE-248 for the EP 3 receptor in HPA, ONO-DI-004 was ineffective on the EP 1 receptor present in HPV while ONO-8713 was the more potent EP 1 antagonist used in this tissue.