[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Apr 1997 · Journal of Cardiovascular Pharmacology
[Show abstract][Hide abstract] ABSTRACT: The prostacyclin mimetics BMY 45778 (3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid), BMY 42393 (2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid) and EP 185 (rac 5-endo-(6'-carboxyhex-2'Z-enyl)-6-exo-(p-methoxyphenyl- phenyl-methylazino)-bicyclo[2.2.2]oct-2-ene) inhibited rat neutrophil aggregation stimulated by N-formyl-methionyl-leucyl-phenylalanine (IC50 = 20, 462, and 1195 nM respectively). In contrast only BMY 45778 (1-10 microM) produced any significant inhibition (10-20%) of the spontaneous activity of rat colon. BMY 45778 (10 microM) also attenuated the inhibitory effect of the prostacyclin analogue cicaprost on rat colon, whereas BMY 42393 and EP 185 did not. BMY 45778 appears to be a low affinity partial agonist at prostacyclin receptors on rat colon and its low potency in rat colon compared with rat neutrophils suggests the presence of a different prostacyclin receptor located on enteric neurones.
No preview · Article · Jun 1995 · European Journal of Pharmacology