title: Effects of CGS 21680, a selective adenosine A2A receptor agonist, on allergic airways inflammation in the rat.
abstract: We have investigated the effect of 2(4-((2-carboxymethyl)phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), a potent and selective agonist at adenosine A2A receptors, on pulmonary inflammation induced by allergen challenge in the ovalbumin-sensitised, Brown Norway rat. Aerosol administration of ovalbumin (5 mg x ml(-1) for 60 min; calculated dose 0.4 mg x kg(-1)) induced increases in bronchoalveolar lavage fluid leukocyte numbers, protein content and myeloperoxidase and eosinophil peroxidase activities measured 24 h post challenge. CGS 21680 (10 and 100 microg x kg(-1) given intratracheally (i.t.) 30 min before and 3 h after allergen challenge) inhibited dose-dependently all the parameters of inflammation. Qualitatively similar results were obtained with the glucocorticosteroid, budesonide (0.1, 1 and 10 mg x kg(-1) given 3 h prior to ovalbumin challenge). CGS 21680 given i.t. reduced blood pressure in anaesthetised rats at similar doses to those at which anti-inflammatory effects were manifested. Both the anti-inflammatory and hypotensive responses to CGS 21680 were blocked by pretreatment with the selective adenosine A2A receptor antagonist, 4-(2-(7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a(1,3,5)triazin-5-yl amino)ethyl)phenol (ZM 241385), 3 mg x kg(-1) p.o., 1 h prior to the agonist. Thus, CGS 21680 manifests broad-spectrum anti-inflammatory activity in a model of allergic asthma in the Brown Norway rat through activation of adenosine A2A receptors. The striking similarity to budesonide, a clinically used anti-inflammatory agent, suggests that adenosine A2A receptor agonists may be useful alternatives to glucocorticosteroids in the treatment of asthma.
authors.affiliation: Research Department, Novartis Pharma AG, WSJ-386.510, CH-4002, Basel, Switzerland. john_r.fozard@pharma.novartis.com
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ellis
authors.forename: Maria F
authors.initials: MF
authors.lastname: Villela Dantas
authors.forename: Bruno
authors.initials: B
authors.lastname: Tigani
authors.forename: Lazzaro
authors.initials: L
authors.lastname: Mazzoni
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000485:Allergens / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D019819:Budesonide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010627:Phenethylamines / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D011914:Rats, Inbred BN; D043705:Receptor, Adenosine A2A; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000485:Allergens; D000893:Anti-Inflammatory Agents; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019819:Budesonide; D010047:Ovalbumin; D000241:Adenosine