cicaprost and 17-20-dimethylisocarbacyclin

1. Our study shows that the prostacyclin analogues AFP-07 and cicaprost are moderately potent agonists for prostanoid EP(4) receptors, in addition to being highly potent IP(1) receptor agonists. Both activities were demonstrated on piglet and rabbit saphenous veins, which are established EP(4) preparations. 2. On piglet saphenous vein, PGE(2) was 6.1, 24, 96, 138, 168 and 285 times respectively more potent than AFP-07, cicaprost, PGI(2), iloprost, carbacyclin and TEI-9063 in causing relaxation. Another prostacyclin analogue taprostene did not induce maximum relaxation (21 - 74%), and did not oppose the action of PGE(2). The EP(4) receptor antagonist AH 23848 (30 microM) blocked relaxant responses to PGE(2) (dose ratio=8.6+/-1.3, s.e.mean) to a greater extent than cicaprost (4.9+/-0.7) and AFP-07 (3.8+/-0.8), had variable effects on TEI-9063-induced relaxation (3.7+/-1.5), and had no effect on taprostene responses (<2.0). 3. On rabbit saphenous vein, AH 23848 blocked the relaxant actions of PGE(2), AFP-07, cicaprost, iloprost and carbacyclin to similar extents. 4. AFP-07, cicaprost and TEI-9063 showed high IP(1) relaxant potency on piglet carotid artery, rabbit mesenteric artery and guinea-pig aorta, with AFP-07 confirmed as the most potent IP(1) agonist reported to date. AH 23848 did not block cicaprost-induced relaxation of piglet carotid artery. EP(3) contractile systems in these preparations can confound IP(1) agonist potency estimations. 5. Caution is urged when using AFP-07 and cicaprost to characterize IP(1) receptors in the presence of EP(4) receptors. Taprostene may be a lead to a highly selective IP(1) receptor agonist.

Topics: Alprostadil; Animals; Biphenyl Compounds; Blood Vessels; Carotid Arteries; Dinoprostone; Dose-Response Relationship, Drug; Endothelium, Vascular; Epoprostenol; Guinea Pigs; In Vitro Techniques; Male; Mesenteric Arteries; Mice; Rabbits; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Saphenous Vein; Swine; Vasoconstriction; Vasodilation

The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.

Topics: Acetates; Aged; Cardiovascular Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoprostenol; Fatty Acids; Humans; Iloprost; Imidazoles; Indoles; Middle Aged; Muscle, Smooth, Vascular; Oxazoles; Phenoxyacetates; Platelet Aggregation Inhibitors; Prostaglandins, Synthetic; Pulmonary Artery; Receptors, Epoprostenol; Receptors, Prostaglandin; Structure-Activity Relationship; Vasoconstrictor Agents; Vasodilator Agents