title: A novel irreversible antagonist of the A1-adenosine receptor.
abstract: We determined the effects of 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanth ine (FSCPX), a putative irreversible antagonist of the A1-adenosine receptor, on cardiac A1-adenosine receptor-mediated responses and on the specific binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]CPX) to guinea pig cardiac and brain membranes. FSCPX (5 microM) completely reversed the increase in K+ current of guinea pig atrial myocytes caused by 100 microM adenosine (259 +/- 30 to 20 +/- 7 pA) but had no significant effect on K+ currents caused by either 0.5 microM carbachol or 100 microM GTP gamma S. The attenuation of K+ current by FSCPX was both time and concentration dependent and persisted after washout of the antagonist. Pretreatment of atrial myocytes with FSCPX (50 nM) markedly attenuated the activation of K+ current and the inhibition of isoproterenol-stimulated I(Ca,L) caused by adenosine by 90.1% and 84.2%, respectively, but did not alter the responses of atrial myocytes to carbachol. FSCPX (1 microM) irreversibly antagonized the A1-adenosine receptor-mediated increase in atrioventricular nodal conduction time of isolated perfused guinea pig hearts from 10.5 +/- 0.5 to 0.7 +/- 0.6 msec but did not significantly alter the A2-adenosine receptor-mediated decrease in coronary resistance. Preincubation of guinea pig cardiac membranes with 0.1, 1.0, or 3.0 microM FSCPX for 30 min reduced the Bmax of [3H]CPX binding by 41 +/- 10%, 67 +/- 6%, and 80 +/- 1% (mean +/- standard error, three experiments), respectively, with no significant change in the Kd. Similarly, 0.1 and 1.0 microM FSCPX irreversibly reduced the binding of [3H]CPX to guinea pig forebrain membranes by 65 +/- 5% and 83 +/- 2% (four experiments), respectively, but did not reduce the binding of [3H]CGS 21680, an A2a-adenosine receptor agonist, to striatal membranes. FSCPX did not affect the potency of 5'-guanylylimidodiphosphate to inhibit the binding of [3H]CCPA, an A1-adenosine receptor agonist, to brain membranes. The results indicate that FSCPX is a specific, irreversible, A1-adenosine subtype-selective receptor antagonist.
authors.affiliation: Department of Pharmacology, University of Florida, Gainesville, USA.
authors.forename: M
authors.initials: M
authors.lastname: Srinivas
authors.forename: J C
authors.initials: JC
authors.lastname: Shryock
authors.forename: P J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: J
authors.initials: J
authors.lastname: Ruble
authors.forename: S P
authors.initials: SP
authors.lastname: Baker
authors.forename: L
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006325:Heart Atria; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C100640:8-cyclopentyl-3-(3-((4-(fluorosulfonyl)benzoyl)oxy)propyl)-1-propylxanthine; D006165:Guanylyl Imidodiphosphate; C053907:8-cyclopentyl-1,3-dimethylxanthine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002217:Carbachol; D013806:Theophylline; D019204:GTP-Binding Proteins; D000241:Adenosine; D007545:Isoproterenol