title: N-0861 selectively antagonizes adenosine A1 receptors in vivo.
abstract: Experiments were performed to determine the antagonistic actions of (+/-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) at A1 and A2 adenosine receptors in vivo, and to evaluate the pharmacodynamics of the observed responses. The selectivity of antagonism of A1 vs. A2 receptors by N-0861 was evaluated by generating dose-response curves to adenosine-induced bradycardia (A1 effect), and vasodilation in the in situ constant-flow perfused rat hindquarter vasculature (A2 effect). N-0861, at doses greater than or equal to 1 mumol/kg + 0.04 mumol/kg per min, i.v. produced dose-related rightward shifts of the A1 dose-response curve, but had no effect on the A2 dose-response curve at doses as high as 100 mumol/kg, i.v. In contrast, the non-selective A1/A2 adenosine receptor antagonist 8-phenyltheophylline antagonized both A1 and A2 receptor-mediated responses to adenosine. The minimum effective i.v. dose and the duration of action of N-0861 were determined by evoking bradycardic responses to i.v. adenosine (A1 effect) in anesthetized, vagotomized, beta-blocked rats before and after single bolus doses of vehicle or N-0861 (0.3, 0.6, 1.0, 3.0 or 10.0 mumol/kg). The lowest i.v. dose of N-0861 to antagonize A1 receptor-mediated bradycardia was 0.3 mumol/kg i.v.; the duration of effect ranged from 1 min (following 0.3-1 mumol/kg) to approximately 2.5 h (following 10 mumol/kg). N-0861 is a selective (by greater than or equal to 333-fold) antagonist of adenosine A1 receptors.
authors.affiliation: Department of Pharmacology, Whitby Research, Inc., Richmond, VA 23261-7426.
authors.forename: R J
authors.initials: RJ
authors.lastname: Barrett
authors.forename: D A
authors.initials: DA
authors.lastname: Droppleman
authors.forename: K F
authors.initials: KF
authors.lastname: Wright
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009636:Norbornanes / Q000494:pharmacology*; D058914:Purinergic Antagonists; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D009636:Norbornanes; D058914:Purinergic Antagonists; C073387:N 0861; D013806:Theophylline; C028322:8-phenyltheophylline; D000225:Adenine; D000241:Adenosine