Activation and Desensitization of Rat A₃-Adenosine Receptors by Selective Adenosine Derivatives and...

Strategy, Management and Health PolicyVenture Capital Enabling TechnologyPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV Xanthine and adenosine derivatives, known to bind to recombinant rat A₃ adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A₃ receptor-stimulated binding of [³⁵S]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 A₃ receptors with full efficacy, appeared to be a partial agonist at the rat A₃ 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 A₃ receptors, as indicated by loss of [³⁵S]GTPγS binding. At A₁ 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 A₃ receptors. A new xanthine riboside (3'-deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A₃ receptors and an antagonist at rat A₁ receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A₃) and block another subtype (A₁) within the same species.