Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP1 activity

作者：Syed Nawazish i Husain; Jones Robert L^*

来源：Prostaglandins, Leukotrienes and Essential Fatty Acids, 2015, 95: 19-29.

DOI：10.1016/j.plefa.2014.11.011

• Smooth muscle relaxation
• Prostanoid IP receptor
• Prostanoid EP receptor
• Prostanoid DP receptor
• Treprostinil
• Naxaprostene

In this study, the inhibitory profiles of the prostacyclin analogues treprostinil and naxaprostene on several isolated smooth muscle preparations have been investigated. Treprostinil was an agonist for prostanoid DP1, EP2 and IP receptors, but not EP4 receptors; its DP1 potency was only 3-4 times less than PGD(2) itself. Naxaprostene was much more selective for IP receptors and tended towards partial agonism. Treprostinil is a 13,14-dihydro analogue and the role of conformation around C12-15 in controlling agonist specificity is debated; the synthesis of new analogues is proposed and possible clinical usage discussed. In terms of selective prostanoid antagonists employed, BW-A868C/MK-0524 (DP1), ACA-23 (EP2) and GW-627368 (EP4) were found fit for purpose. However, the IP antagonist RO-1138452 was compromised by alpha(1) and alpha(2)-adrenoceptor-mediated contractile activity on rat tail artery and antimuscarinic activity on mouse trachea. There is a need for IP receptor antagonists with better selectivity and higher affinity.

• 出版日期2015-4