title: Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models.
abstract: The effects of a novel adenosine A(3) receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10(-5)M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride] (10(-7)M) increased the antigen response up to 61 ± 3.0% and 88 ± 5.2% of maximal contraction, respectively. The agonists of adenosine A(1) and A(2) adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5'-N-ethylcarboxamidoadenosine], R-PIA [N(6)-R-phenylisopropyladenosine], and CGS21680 (10(-7)M) were ineffective. In vivo intravenous adenosine (600 μg/kg) and AB-MECA (30 μg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214 ± 13.0% and 220 ± 15.2%, respectively. SSR161421 in vitro (IC(50)=5.9 × 10(-7)M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED(50)=0.008 mg/kg) or oral (ED(50)=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3 × 10(-6)M) decreased the AUC of the antigen-induced contraction-time curve to 20.8 ± 5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC(50) values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.
authors.affiliation: Sanofi Co. Ltd, H-1045 Budapest Tó utca 1-5, Hungary. endre.mikus@labmagister.com
authors.forename: Endre G
authors.initials: EG
authors.lastname: Mikus
authors.forename: Judit
authors.initials: J
authors.lastname: Szeredi
authors.forename: Kinga
authors.initials: K
authors.lastname: Boer
authors.forename: Géza
authors.initials: G
authors.lastname: Tímári
authors.forename: Michel
authors.initials: M
authors.lastname: Finet
authors.forename: Péter
authors.initials: P
authors.lastname: Aranyi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Galzin
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000276:immunology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000276:immunology
chemical_list: C583157:4-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide; D058918:Adenosine A3 Receptor Antagonists; D000634:Aminoquinolines; D000941:Antigens; D001549:Benzamides; C089722:N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide; D000241:Adenosine