title: Pharmacodynamics of ZM 241385, a potent A2a adenosine receptor antagonist, after enteric administration in rat, cat and dog.
abstract: 4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5] triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1-10 mg kg-1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg-1 min-1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg-1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6-1.0 mg kg-1, i.v.) by 94% after 10 mg kg-1 (p.o.) and by up to 74% after 0.3 mg kg-1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg-1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1-10 mg kg-1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg-1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg-1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A2a receptors in the action of adenosine in-vivo.
authors.affiliation: Cardiovascular and Metabolism Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Poucher
authors.forename: J R
authors.initials: JR
authors.lastname: Keddie
authors.forename: R
authors.initials: R
authors.lastname: Brooks
authors.forename: G R
authors.initials: GR
authors.lastname: Shaw
authors.forename: D
authors.initials: D
authors.lastname: McKillop
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002415:Cats; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D013045:Species Specificity; D013806:Theophylline / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D058915:Purinergic P1 Receptor Antagonists; D014227:Triazines; D014230:Triazoles; D014665:Vasodilator Agents; C097270:ZM 241385; D013806:Theophylline