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Molecular Pharmacology

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Research ArticleArticle

Synthetic Modification of Prostaglandin F2αIndicates Different Structural Determinants for Binding to the Prostaglandin F Receptor Versus the Prostaglandin Transporter

Victor L. Schuster, Shigekazu Itoh, Steven W. Andrews, Robert M. Burk, June Chen, Karen M. Kedzie, Daniel W. Gil and David F. Woodward
Molecular Pharmacology December 2000, 58 (6) 1511-1516; DOI: https://doi.org/10.1124/mol.58.6.1511
Victor L. Schuster
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Shigekazu Itoh
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Steven W. Andrews
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Robert M. Burk
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June Chen
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Karen M. Kedzie
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Daniel W. Gil
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David F. Woodward
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Abstract

Several principles governing the binding of E series prostaglandins to EP receptors have emerged in recent years. The C-1 carboxyl group binds electrostatically to a conserved arginine residue in the seventh transmembrane segment of the receptor. Prostaglandin E analogs involving bioisosteric replacements of the carboxyl group, such as acylsulfonamide, are also active. In addition, structurally similar esters may also exhibit similar affinity, presumably by virtue of hydrogen bonding. Other regions of the substrate molecule appear to bind to other domains of EP receptors, either via hydrophobic interactions or by hydrogen bonding. Less information is available about the structural requirements for substrate binding to FP receptors. Prostanoids also bind to the prostaglandin transporter PGT. In this case, a conserved C-1 carboxyl group is critically important, since C-1 esters exhibit little affinity. Here we examined the binding of chemically diverse PGF2α structural analogs to the FP receptor and compared these with binding by the PG transporter. PGT recognized a wide range of anionic substituents. In contrast, the carboxylic acid group was essential for optimal binding to the FP receptor, since replacement by larger moieties with a similar pK a, such as acylsulfonamide and tetrazole, substantially decreased binding affinity. Interestingly, insertion of cyclic substituents in the omega chain increased binding to the FP receptor but reduced affinity for PGT, and substitution for the 15-hydroxyl group produced only a modest reduction in FP receptor binding, but eliminated binding by PGT. Because extracellular PGF2α may compete for binding between FP receptors and PGT, these findings have implications for designing PGF2αanalogs for treating disease states.

Footnotes

    • Received April 24, 2000.
    • Accepted August 18, 2000.
  • Send reprint requests to: Dr. Victor L. Schuster, Renal Division, Ullmann 615, 1300 Morris Park Ave., Bronx, NY 10461. E-mail:schuster{at}aecom.yu.edu

  • 1 A portion of the work was supported by grants (to V.L.S.) from the National Institutes of Health (DK 49688), the National Kidney Foundation, and the American Heart Association (New York City Affiliate).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (6)
Molecular Pharmacology
Vol. 58, Issue 6
1 Dec 2000
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Research ArticleArticle

Synthetic Modification of Prostaglandin F2αIndicates Different Structural Determinants for Binding to the Prostaglandin F Receptor Versus the Prostaglandin Transporter

Victor L. Schuster, Shigekazu Itoh, Steven W. Andrews, Robert M. Burk, June Chen, Karen M. Kedzie, Daniel W. Gil and David F. Woodward
Molecular Pharmacology December 1, 2000, 58 (6) 1511-1516; DOI: https://doi.org/10.1124/mol.58.6.1511

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Research ArticleArticle

Synthetic Modification of Prostaglandin F2αIndicates Different Structural Determinants for Binding to the Prostaglandin F Receptor Versus the Prostaglandin Transporter

Victor L. Schuster, Shigekazu Itoh, Steven W. Andrews, Robert M. Burk, June Chen, Karen M. Kedzie, Daniel W. Gil and David F. Woodward
Molecular Pharmacology December 1, 2000, 58 (6) 1511-1516; DOI: https://doi.org/10.1124/mol.58.6.1511
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