Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta

R. Jones, D. Woodward, J.F. Wang

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10 Citations (Scopus)


EP3 receptor antagonists are a recent addition to the prostanoid ligand armoury. We have examined the profiles of two such agents, L-798106 (([(2E)-N-[(5-bromo- 2-methoxyphenyl)-sulphonyl]-3-[2¢-(2-naphthyl-methyl)phenyl]acrylamide) and its 5¢-chloro analogue L-826266 (Belley et al., 2006). Muscle tension in isolated preparations of thoracic aorta and vas deferens (electrical-field stimulation) from Dunkin-Hartley male guinea-pigs (600 - 800 g) was recorded. EP3 agonism (17- phenyl PGE2 or ONO-AE-248) on aorta was measured under priming with phenylephrine (500 - 1500 nM). Selectivity of prostanoid ligands was confirmed using human recombinant prostanoid receptor FLIPR assays (co-transfection with chimeric G-protein cDNAs to allow activation of Ca2+flux / HEK-293 EBNA cells). L-798106 and L-826266 (50-1000 nM) slowly inhibited established contraction of the guinea-pig aorta to the primed EP3 agonist (incomplete at 60 min) in contrast to faster block on vas deferens. Exposure of aorta to antagonist for 3 h resulted in much greater block and parallel displacement of the EP3 agonist log concentrationresponse curve; pA2 value = 7.58 and 7.96 respectively. Phentolamine (100 nM) rapidly inhibited phenylephrine / EP3 agonist responses. The potent TP antagonist BMS-180291 (Ifetroban) also slowly blocked U-46619 contraction of the aorta at concentrations of 0.3-3 nM (pA2 = 9.76), whereas the less potent antagonists EP-045 and EP-092 had faster onsets. Studies on histamine H1 antagonists showed that doxepin (pA2 = 9.6), terfenadine (pA2 = 7.9) and astemizole (7.5) were slow to reach steady-state block, while (+)-chlorpheniramine (9.1) was faster and diphenhydramine (7.8) even faster. The slow kinetics of L-798106, L-826266, terfenadine and astemizole, which have modest affinities, may relate to their very high lipophilicity (clogP = 6.87, 7.39, 6.54 and 5.64 repectively; ChemAxon software). In contrast, the slow kinetics of BMS-180291 and doxepin (cLogP = 3.60 and 3.59) are probably a consequence of their high affinity for TP and H1 receptors respectively. Care is needed in using highly lipophiic EP3 antagonists to elucidate receptor involvement.
Original languageEnglish
Number of pages0
Publication statusPublished - Aug 2008
EventFederation of European Pharmacological Societies Congress - Manchester, UK
Duration: 13 Jul 200817 Jul 2008


ConferenceFederation of European Pharmacological Societies Congress
CityManchester, UK


  • pharmacology
  • kinetics
  • chemistry

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