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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Keith Morrison, Roland Ernst, Patrick Hess, Rolf Studer and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics October 2010, 335 (1) 249-255; DOI: https://doi.org/10.1124/jpet.110.169748
Keith Morrison
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Roland Ernst
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Patrick Hess
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Rolf Studer
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Martine Clozel
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Abstract

Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI2) receptor (IP receptor) agonist that is chemically distinct from PGI2 and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI2 can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI2 analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP1) > prostaglandin E receptor 3 (EP3), IP receptor > prostaglandin D2 receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10−3 M. In contrast, the PGI2 analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10−4 M). Contraction to all PGI2 analogs was mediated via activation of EP3 receptors, although EP1 receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.169748.

  • ABBREVIATIONS:

    PGI2
    prostacyclin
    IP receptor
    PGI2 receptor
    EP1 receptor
    prostaglandin E receptor 1
    EP3 receptor
    prostaglandin E receptor 3
    DP receptor
    prostaglandin D2 receptor 1
    TP receptor
    thromboxane receptor
    PAH
    pulmonary arterial hypertension
    PGF2α
    prostaglandin F2α
    QPCR
    quantitative polymerase chain reaction
    F receptor
    prostaglandin F receptor
    ACT-333679
    {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid
    selexipag (NS-304, ACT-293987)
    2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide
    CAY10441
    4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine
    DBTSA
    (2E)-3-(3′,4′-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide
    SC19220
    8-chloro-dibenz[b,f][1,4]oxazepine-10(11H)-carboxy-(2-acetyl)hydrazide
    SC51322
    8-chloro-2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide, dibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid hydrazide
    GR32191
    (4Z)-7-[(1R,2R,3S,5S)-5-([1, 1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid
    AL8810
    9α,15R-dihydroxy-11β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid
    BWA868C
    3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidineheptanoic acid.

  • Received April 28, 2010.
  • Accepted July 20, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Keith Morrison, Roland Ernst, Patrick Hess, Rolf Studer and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 249-255; DOI: https://doi.org/10.1124/jpet.110.169748

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Keith Morrison, Roland Ernst, Patrick Hess, Rolf Studer and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 249-255; DOI: https://doi.org/10.1124/jpet.110.169748
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