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

Research output: Contribution to conferencePoster

Abstract

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.
LanguageEnglish
Pages73-73
Number of pages0
Publication statusPublished - Aug 2008
EventFederation of European Pharmacological Societies Congress - Manchester, UK
Duration: 13 Jul 200817 Jul 2008

Conference

ConferenceFederation of European Pharmacological Societies Congress
CityManchester, UK
Period13/07/0817/07/08

Fingerprint

Prostaglandins
Aorta
Guinea Pigs
Astemizole
Doxepin
Terfenadine
Vas Deferens
Phenylephrine
Histamine H1 Antagonists
Chlorpheniramine
Ligands
Diphenhydramine
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Histamine H1 Receptors
Muscle Tonus
Acrylamide
Phentolamine
HEK293 Cells
Thoracic Aorta
GTP-Binding Proteins

Keywords

  • pharmacology
  • kinetics
  • chemistry

Cite this

Jones, R., Woodward, D., & Wang, J. F. (2008). Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta. 73-73. Poster session presented at Federation of European Pharmacological Societies Congress, Manchester, UK, .
Jones, R. ; Woodward, D. ; Wang, J.F. / Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta. Poster session presented at Federation of European Pharmacological Societies Congress, Manchester, UK, .
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Jones, R, Woodward, D & Wang, JF 2008, 'Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta' Federation of European Pharmacological Societies Congress, Manchester, UK, 13/07/08 - 17/07/08, pp. 73-73.

Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta. / Jones, R.; Woodward, D.; Wang, J.F.

2008. 73-73 Poster session presented at Federation of European Pharmacological Societies Congress, Manchester, UK, .

Research output: Contribution to conferencePoster

TY - CONF

T1 - Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta

AU - Jones, R.

AU - Woodward, D.

AU - Wang, J.F.

PY - 2008/8

Y1 - 2008/8

N2 - 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.

AB - 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.

KW - pharmacology

KW - kinetics

KW - chemistry

UR - http://www.ephar2008.org/

UR - http://www.ephar2008.org/downloads/EPHAR2008_Final_Programme.pdf

UR - http://www.blackwellpublishing.com/pdf/j.1472-8206.2008.00596.pdf

M3 - Poster

SP - 73

EP - 73

ER -

Jones R, Woodward D, Wang JF. Investigation of the slow kinetics of the prostanoid ep3 receptor antagonists l-798106 and l-826266 on guinea-pig aorta. 2008. Poster session presented at Federation of European Pharmacological Societies Congress, Manchester, UK, .