title: Assessing the agonist profiles of the prostacyclin analogues treprostinil and naxaprostene, particularly their DP₁ activity.
abstract: 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 PGD2 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 α1 and α2-adrenoceptor-mediated contractile activity on rat tail artery and anti-muscarinic activity on mouse trachea. There is a need for IP receptor antagonists with better selectivity and higher affinity.
authors.affiliation: Cardiovascular Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
authors.forename: Nawazish-i-Husain
authors.initials: NI
authors.lastname: Syed
authors.affiliation: Cardiovascular Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK. Electronic address: robertlesliejones@btinternet.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jones
mesh_terms: D000818:Animals; D011464:Epoprostenol / Q000819:agonists / Q000031:analogs & derivatives* / Q000737:chemistry; D006827:Hydantoins / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006827:Hydantoins; D007211:Indoles; C518174:MK-0524; D011982:Receptors, Prostaglandin; C058848:BW A868C; C050548:naxaprostene; D011464:Epoprostenol; C427248:treprostinil
keywords: Naxaprostene; Prostanoid DP receptor; Prostanoid EP receptor; Prostanoid IP receptor; Smooth muscle relaxation; Treprostinil