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Activation and desensitization of rat A 3 ‐adenosine receptors by selective adenosine derivatives and xanthine‐7‐ribosides
Author(s) -
Park Kyungsun,
Hoffmann Carsten,
Kim Hea Ok,
Padgett William L.,
Daly John W.,
Brambilla Roberta,
Motta Cristina,
Abbracchio Maria P.,
Jacobson Kenneth A.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199806/07)44:2/3<97::aid-ddr7>3.0.co;2-5
Subject(s) - agonist , adenylyl cyclase , adenosine receptor , receptor , adenosine , adenosine a2b receptor , chemistry , homologous desensitization , adenosine a3 receptor , adenosine a1 receptor , chinese hamster ovary cell , partial agonist , xanthine , pharmacology , biology , biochemistry , medicine , enzyme
Xanthine and adenosine derivatives, known to bind to recombinant rat A 3 adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A 3 receptor‐stimulated binding of [ 35 S]GTPγS in rat RBL‐2H3 cell membranes. 1,3‐Dibutylxanthine‐7‐riboside‐5′‐N‐methylcarboxamide (DBXRM, 7b), previously shown to inhibit adenylyl cyclase via rat A 3 receptors with full efficacy, appeared to be a partial agonist at the rat A 3 receptor of RBL‐2H3 cells. Full agonists, such as Cl‐IB‐MECA or I‐AB‐MECA, were more potent and effective than the partial agonist DBXRM in causing desensitization of rat A 3 receptors, as indicated by loss of [ 35 S]GTPγS binding. At A 1 receptors, antagonism of agonist‐elicited inhibition of rat adipocyte adenylyl cyclase was observed for several xanthine‐7‐riboside derivatives that had been shown to be full agonists at rat A 3 receptors. A new xanthine riboside (3′‐deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A 3 receptors and an antagonist at rat A 1 receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A 3 ) and block another subtype (A 1 ) within the same species. Drug Dev. Res. 44:97–105, 1998. © 1998 Wiley‐Liss, Inc. This is a US Government work and, as such, is in the public domain in the United States of America.