Dataset Information

Interaction of prostanoid EP? and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE?.

ABSTRACT: BACKGROUND AND PURPOSE: Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E? (DX-DM PGE?) on pig cerebral artery when used as a selective EP? receptor agonist. This study investigated the selectivity profile of DX-DM PGE?, focusing on the interaction between its EP? and TP (thromboxane A?-like) agonist activities. EXPERIMENTAL APPROACH: Contraction of guinea-pig trachea (EP? system) and aorta (EP? and TP systems) was measured in conventional organ baths. KEY RESULTS: Strong contraction of guinea-pig aorta to sulprostone and 17-phenyl PGE? (EP? agonists) was only seen under priming with a second contractile agent such as phenylephrine, histamine or U-46619 (TP agonist). In contrast, DX-DM PGE? induced strong contraction, which on the basis of treatment with (DG)-3ap (EP? antagonist) and/or BMS-180291 (TP antagonist) was attributed to self-synergism arising from co-activation of EP? and TP receptors. EP?/TP self-synergism also accounted for contraction induced by PGF(2?) and its analogues (+)-cloprostenol and latanoprost-FA. DX-DM PGE? also showed significant EP? agonism on guinea-pig trachea as defined by the EP? antagonists SC-51322, (ONO)-5-methyl-1 and AH-6809, although AH-6809 exhibited poor specificity at concentrations ?3 µM. CONCLUSIONS AND IMPLICATIONS: EP?/TP self-synergism, as seen with PGE/PGF analogues in this study, may confound EP? agonist potency comparisons and the characterization of prostanoid receptor systems. The competitive profile of a TP antagonist may be distorted by variation in the silent/overt contraction profile of the EP? system in different studies. The relevance of self-synergism to in vivo actions of natural prostanoid receptor agonists is discussed.

SUBMITTER: Jones RL

PROVIDER: S-EPMC3031070 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interaction of prostanoid EP₃ and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE₂.

Jones R L RL Woodward D F DF

British journal of pharmacology 20110101 2

<h4>Background and purpose</h4>Surprisingly high contractile activity was reported for 11-deoxy-16,16-dimethyl prostaglandin E₂ (DX-DM PGE₂) on pig cerebral artery when used as a selective EP₃ receptor agonist. This study investigated the selectivity profile of DX-DM PGE₂, focusing on the interaction between its EP₃ and TP (thromboxane A₂-like) agonist activities.<h4>Experimental approach</h4>Contraction of guinea-pig trachea (EP₁ system) and aorta (EP₃ and TP systems) was measured in convention ...[more]

PMID: 20955363

Similar Datasets

Project description:BackgroundThe EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP.ResultsRank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP4 receptor and ligands including PGE2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models.ConclusionsThis work has generated a set of novel homology models of the rEP4 and hEP4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE1 ≈ PGE2 > 11-deoxy-PGE1 ≈ 11-dexoy-PGE2 > 8-aza-11-deoxy-PGE1. This rank-ordering matches closely with the rEP4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.

Dataset Information

Interaction of prostanoid EP? and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE?.

Publications

Interaction of prostanoid EP₃ and TP receptors in guinea-pig isolated aorta: contractile self-synergism of 11-deoxy-16,16-dimethyl PGE₂.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets