Synthetic modification of prostaglandin F(2α), indicates 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, David F. Woodward

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 PGF(2α) 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 PGF(2α) may compete for binding between FP receptors and PGT, these findings have implications for designing PGF(2α) analogs for treating disease states.

Original languageEnglish (US)
Pages (from-to)1511-1516
Number of pages6
JournalMolecular Pharmacology
Volume58
Issue number6
StatePublished - 2000

Fingerprint

Synthetic Prostaglandins F
Prostaglandin Receptors
Prostaglandins F
Prostaglandins
Hydrogen Bonding
Synthetic Prostaglandins E
Carboxylic Acids
Prostaglandins E
Hydrophobic and Hydrophilic Interactions
Hydroxyl Radical
Arginine
prostaglandin F2alpha receptor
Esters

ASJC Scopus subject areas

  • Pharmacology

Cite this

Synthetic modification of prostaglandin F(2α), indicates different structural determinants for binding to the prostaglandin F receptor versus the prostaglandin transporter. / Schuster, Victor L.; Itoh, Shigekazu; Andrews, Steven W.; Burk, Robert M.; Chen, June; Kedzie, Karen M.; Gil, Daniel W.; Woodward, David F.

In: Molecular Pharmacology, Vol. 58, No. 6, 2000, p. 1511-1516.

Research output: Contribution to journalArticle

Schuster, Victor L. ; Itoh, Shigekazu ; Andrews, Steven W. ; Burk, Robert M. ; Chen, June ; Kedzie, Karen M. ; Gil, Daniel W. ; Woodward, David F. / Synthetic modification of prostaglandin F(2α), indicates different structural determinants for binding to the prostaglandin F receptor versus the prostaglandin transporter. In: Molecular Pharmacology. 2000 ; Vol. 58, No. 6. pp. 1511-1516.
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