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Volume 225, Issue 1-2 p. 97-102
Full-length article
Free Access

Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors

Kenneth A. Jacobson

Corresponding Author

Kenneth A. Jacobson

Laboratory of Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

K.A. Jacobson, Laboratory of Chemistry, Bldg 8A, Rm B1A-17, NIDDK, NIH, Bethesda, MD 20892, USASearch for more papers by this author
Jeffrey Zimmet

Jeffrey Zimmet

Laboratory of Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

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Richard Schulick

Richard Schulick

Laboratory of Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

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Suzanne Barone

Suzanne Barone

Laboratory of Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

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John W. Daly

John W. Daly

Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

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Kenneth L. Kirk

Kenneth L. Kirk

Laboratory of Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA

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First published: December 10, 1987
Citations: 10

Abstract

Chemically functionalized congeners of N6-phenyladenosine and 1,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglycerides, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosine binding to A1-adenosine receptors in rat cerebral cortex membranes. A xanthine-phosphatidylethanolamine conjugate bound with a K i value of 19 nM. Various xanthine esters of low potency are potential prodrugs. Amides of an adenosine amine congener (ADAC) with 18-carbon fatty acids exhibited K i values at A1-adenosine receptors of 70 pM, representing a 130-fold enhancement over the affinity of the corresponding acetyl amide. The very high affinity of adenosine-lipid conjugates may be due to stabilization of these adducts in the phospholipid microenvironment of the receptor protein.