Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors

Veeresa Gududuru, Kui Zeng, Ryoko Tsukahara, Natalia Makarova, Yuko Fujiwara, Kathryn R. Pigg, Daniel L. Baker, Gabor Tigyi, Duane Miller

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Darmstoff describes a family of gut smooth muscle-stimulating acetal phosphatidic acids initially isolated and characterized from the bath fluid of stimulated gut over 50 years ago. Despite similar structural and biological profiles, Darmstoff analogs have not previously been examined as potential LPA mimetics. Here, we report a facile method for the synthesis of potassium salts of Darmstoff analogs. To understand the effect of stereochemistry on lysophosphatidic acid mimetic activity, synthesis of optically pure stereoisomers of selected Darmstoff analogs was achieved starting with chiral methyl glycerates. Each Darmstoff analog was evaluated for subtype-specific LPA receptor agonist/antagonist activity, PPARγ activation, and autotaxin inhibition. From this study we identified compound 12 as a pan-antagonist and several pan-agonists for the LPA 1-3 receptors. Introduction of an aromatic ring in the lipid chain such as analog 22 produced a subtype-specific LPA 3 agonist with an EC 50 of 692 nM. Interestingly, regardless of their LPA 1/2/3 ligand properties all of the Darmstoff analogs tested activated PPARγ. However, these compounds are weak inhibitors of autotaxin. The results indicate that Darmstoff analogs constitute a novel class of lysophosphatidic acid mimetics.

Original languageEnglish (US)
Pages (from-to)451-456
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number2
DOIs
StatePublished - Jan 15 2006

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Lysophosphatidic Acid Receptors
Peroxisome Proliferator-Activated Receptors
Acetals
Phosphatidic Acids
Stereochemistry
Stereoisomerism
darmstoff
Baths
Smooth Muscle
Muscle
Potassium
Salts
Chemical activation
Ligands
Lipids
Fluids

All Science Journal Classification (ASJC) codes

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

Cite this

Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors. / Gududuru, Veeresa; Zeng, Kui; Tsukahara, Ryoko; Makarova, Natalia; Fujiwara, Yuko; Pigg, Kathryn R.; Baker, Daniel L.; Tigyi, Gabor; Miller, Duane.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 2, 15.01.2006, p. 451-456.

Research output: Contribution to journalArticle

Gududuru, Veeresa ; Zeng, Kui ; Tsukahara, Ryoko ; Makarova, Natalia ; Fujiwara, Yuko ; Pigg, Kathryn R. ; Baker, Daniel L. ; Tigyi, Gabor ; Miller, Duane. / Identification of Darmstoff analogs as selective agonists and antagonists of lysophosphatidic acid receptors. In: Bioorganic and Medicinal Chemistry Letters. 2006 ; Vol. 16, No. 2. pp. 451-456.
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