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

Jones, R. and Woodward, D. and Wang, J.F. (2008) Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta. In: Federation of European Pharmacological Societies Congress, 2008-07-13 - 2008-07-17.

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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.