Adenosine analogs with covalently attached lipids have enhanced potency at A1-adenosine receptors.
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 Ki 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 Ki 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.
Laboratory of Chemistry, NIDDK, Bethesda, MD 20892.
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Jacobson
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Zimmet
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Schulick
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Barone
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Daly
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Kirk
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004075:Diglycerides / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D050356:Lipid Metabolism; D010660:Phenylisopropyladenosine / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism*; D014970:Xanthines / Q000378:metabolism
D000814:Aniline Compounds; D004075:Diglycerides; D005227:Fatty Acids; D010714:Phosphatidylethanolamines; D011355:Prodrugs; D011983:Receptors, Purinergic; D014970:Xanthines; C008840:N(6)-phenyladenosine; D010660:Phenylisopropyladenosine; C049140:1,3-dipropyl-8-phenylxanthine; D000241:Adenosine