ACTIVATION AND DESENSITIZATION OF RAT A(3)-ADENOSINE RECEPTORS BY SELECTIVE ADENOSINE DERIVATIVES AND XANTHINE-7-RIBOSIDES

Xanthine and adenosine derivatives, known to bind to recombinant rat A (3) adenosine receptors stably expressed in Chinese hamster ovary cell s, were characterized in a functional assay consisting of activation o f A(3) receptor-stimulated binding of [S-35]GTP gamma S in rat RBL-2H3 cell membranes. -Dibutylxanthine-7-riboside-5'-N-methylcarboxamide (D BXRM, 7b), previously shown to inhibit adenylyl cyclase via rat A(3) r eceptors with full efficacy, appeared to be a partial agonist at the r at A(3) receptor of RBL-2H3 cells. Full agonists, such as Cl-IB-MECA o r I-AB-MECA, were more potent and effective than the partial agonist D BXRM in causing desensitization of rat A(3) receptors, as indicated by loss of [S-35]GTP gamma S binding. At A(1) receptors, antagonism of a gonist-elicited inhibition of rat adipocyte adenylyl cyclase was obser ved for several xanthine-7-riboside derivatives that had been shown to be full agonists at rat A(3) receptors. A new xanthine riboside (3'-d eoxyDBXRM, 7c) was synthesized and found to be a partial agonist at ra t A(3) receptors and an antagonist at rat A(1) receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor sub type (A(3)) and block another subtype (A(1)) within the same species. Drug Dev. Res. 44:97-105, 1998. (C) 1998 Wiley-Liss, Inc.(dagger)