title: Activation and Desensitization of Rat A3-Adenosine Receptors by Selective Adenosine Derivatives and Xanthine-7-Ribosides.
abstract: 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 A3adenosine receptors stably expressed in Chinese hamster ovary cells, were characterized in a functional assay consisting of activation of A3receptor-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 A3receptors with full efficacy, appeared to be a partial agonist at the rat A3receptor 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 A3receptors, as indicated by loss of [35S]GTPγS binding. At A1receptors, 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 A3receptors. A new xanthine riboside (3'-deoxyDBXRM, 7c) was synthesized and found to be a partial agonist at rat A3receptors and an antagonist at rat A1receptors. Thus, it is possible for the same compound to stimulate one adenosine receptor subtype (A3) and block another subtype (A1) within the same species.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Park
authors.forename: Carsten
authors.initials: C
authors.lastname: Hoffmann
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: William L
authors.initials: WL
authors.lastname: Padgett
authors.forename: John W
authors.initials: JW
authors.lastname: Daly
authors.forename: Roberta
authors.initials: R
authors.lastname: Brambilla
authors.forename: Cristina
authors.initials: C
authors.lastname: Motta
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
keywords: adenosine derivatives; adenylyl cyclase; guanine nucleotides; nucleosides; xanthines