Xanthine-7-Ribosides as Adenosine Receptor Antagonists: Further Evidence for Adenosine'S Anti Mode Of Binding |
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Authors: | P. J. M. van Galen A. P. Ijzerman W. Soudijn |
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Affiliation: | Center for Bio-Pharmaceutical Sciences , PO Box 9502, 2300, RA Leiden, The Netherlands |
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Abstract: | Abstract With the aid of computer graphics methods, we recently developed a model for the antagonist binding site of the adenosine A1 receptor (J. Med. Chem. 1990, 33, 1708-1713). According to this model, xanthines should bind to the receptor in a flipped orientation, i.e. the ring atoms N1, N3, N7 and N9 in adenosine coincide with C2, C6, N9 and N7 respectively in theophylline (FIG. la and 1 b). This implicates that the domain where the ribose moiety of adenosine binds must be adjacent to N7 in xanthines, and furthermore that xanthine-7-ribosides should have affinity for the receptor. To further explore the role of the orientation of the ribose moiety in binding to the receptor, we have synthesized and determined the A1 affinity of the 7-ribosides of theophylline, 13-dipropylxanthine and 1,3-dibutylxanthine (FIG. 1c). The orientation of the ribose moiety was studied with H-NMR spectroscopy and theoretical chemical calculations. |
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