20-Hydroxyeicosatetraenoic acid (20-HETE): Structural determinants for renal vasoconstriction

Ming Yu, Magdalena Alonso-Galicia, Cheng Wen Sun, Richard J. Roman, Naoya Ono, Hitomi Hirano, Tsuyoshi Ishimoto, Y. Krishna Reddy, Kishta Reddy Katipally, Komandla Malla Reddy, V. Raj Gopal, Ji Yu, Mohamed Takhi, J R Falck

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Abstract

The effects of natural and synthetic eicosanoids on the diameter of rat interlobular arteries studied in vitro were compared to that of the potent, endogenous vasoconstrictor 20-HETE. Vasoconstrictor activity was optimum for chain lengths of 20-22 carbons with at least one olefin or epoxide between located between C(13)-C(15) and an oxygen substituent at C(20)-C(22). The presence of Δ (Zou et al. Am. J. Physiol. 1996, 270, R228; Gebremedhin, D. et al. Am. J. Physiol. 1998, 507, 771)-, Δ (Carroll et al. Am. J. Physiol. 1996, 271, R863; Vazquez et al. Life Sci. 1995, 56, 1455)-, or Δ (Imig et al. Hypertension 2000, 35, 307; Lopez et al. Amer. J. Physiol. 2001, 281, F420)-olefins had no influence on the vasoconstrictor response whereas the introduction of a C(7)-thiomethylene enhanced potency. A sulfonamide or alcohol, but not a lactone, could replace the C(1)-carboxylate. These data were used to construct a putative binding domain map of the 20-HETE receptor consisting of: (i) a comparatively open, hydrophilic binding site accommodating the C(1)-functionality; (ii) a hydrophobic trough spanning the olefins; (iii) a shallow pocket containing a critical π-π binding site in the vicinity of the π (Ito et al. Am. J. Physiol. 1998, 274, F395; Quigley, R.; Baum, M.; Reddy, K. M.; Griener, J. C.; Falck, J. R. Am. J. Physiol. 2000, 278, F949)-olefin; and (iv) an oxyphilic binding site proximate to the ω-terminus.

Original languageEnglish (US)
Pages (from-to)2803-2821
Number of pages19
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number13
DOIs
Publication statusPublished - Jul 3 2003

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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