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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Affinities, Selectivities, Potencies, and Intrinsic Activities of Natural and Synthetic Prostanoids Using Endogenous Receptors: Focus on DP Class Prostanoids

Najam A. Sharif, Julie Y. Crider, Shouxi X. Xu and Gary W. Williams
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 321-328;
Najam A. Sharif
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Julie Y. Crider
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Shouxi X. Xu
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Gary W. Williams
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Abstract

The prostanoid receptor-subtype binding affinities, selectivities, potencies, and intrinsic activities of four natural prostanoids and six synthetic DP class prostanoids were determined using binding and functional assays with endogenous receptors. SQ27986 exhibited the highest affinity for the human platelet DP receptor and the best DP receptor selectivity profile. Prostaglandin (PG)D2 was the least DP receptor-selective. The rank order of compound affinities at the DP receptor was SQ27986 (Ki = 10 ± 2 nM) > RS93520 = ZK110841 = BW245C (Ki = 23–26 nM) > ZK118182 (Ki = 50 ± 9 nM) > PGD2 (Ki = 80 ± 5 nM). DP receptor agonists produced cAMP in embryonic bovine tracheal fibroblasts with different potencies (EC50 values in nM): ZK118182 (18 ± 6), RS93520 (28 ± 6), SQ27986 (29 ± 7), ZK110841 (31 ± 7), BW245C (53 ± 16), and PGD2 (98 ± 10). BW245C was more efficacious and RS93520 was less efficacious than PGD2. ZK110841 and ZK118182 exhibited a relatively high potency at the adenylyl cyclase-coupled EP2 receptor in human nonpigmented ciliary epithelial cells but were partial agonists. None of the DP class agonists showed any EP4 receptor functional activity in Chinese hamster ovary cells. The DP receptor antagonist BWA868C competitively antagonized the PGD2-induced cAMP accumulation in embryonic bovine tracheal fibroblast cells (pA2 = 7.83 ± 0.08). The dissociation constants for BWA868C antagonizing PGD2-, BW245C-, and ZK118182-induced cAMP production were quite similar (apparent −logKb = 7.9–8.2, n = 5–9). The pharmacological properties of some natural and numerous DP class synthetic prostanoids have been determined using endogenous receptors.

Footnotes

  • Send reprint requests to: Dr. N. A. Sharif, Technical Director and Head of Molecular Pharmacology Unit, Alcon Research, Ltd. (R2-19), 6201 South Freeway, Fort Worth, TX 76134-2099. E-mail:naj.sharif{at}alconlabs.com

  • Abbreviations:
    AC
    adenylyl cyclase
    CHO
    Chinese hamster ovary
    DMEM
    Dulbecco's modified essential medium
    EBTr
    embryonic bovine tracheal
    IA
    intrinsic activity
    NPE
    nonpigmented ciliary epithelial
    pKb
    apparent −log molar antagonist concentration needed to cause dextral shift of agonist concentration-response curve by 2-fold
    pA2
    −log molar antagonist concentration needed to cause dextral shift of agonist concentration-response curve by 2-fold
    PEI
    polyethyleneimine
    PG
    prostaglandin
    PGI2
    prostacyclin
    • Received September 21, 1999.
    • Accepted January 25, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Affinities, Selectivities, Potencies, and Intrinsic Activities of Natural and Synthetic Prostanoids Using Endogenous Receptors: Focus on DP Class Prostanoids

Najam A. Sharif, Julie Y. Crider, Shouxi X. Xu and Gary W. Williams
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 321-328;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Affinities, Selectivities, Potencies, and Intrinsic Activities of Natural and Synthetic Prostanoids Using Endogenous Receptors: Focus on DP Class Prostanoids

Najam A. Sharif, Julie Y. Crider, Shouxi X. Xu and Gary W. Williams
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 321-328;
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