Evaluation of SSR161421, a novel orally active adenosine A3 receptor antagonist on pharmacology models
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- 作者：Endre G. Mikus ; endre.mikus@labmagister.com ; Judit Szeredi ; Kinga Boer ; Gé ; za Tí ; má ; ri ; Michel Finet ; Pé ; ter Aranyi ; Anne-Marie Galzin
- 关键词：Mast cell ; Ovalbumin-sensitization ; Adenosine A3 receptor ; SSR161421 ; Bronchoconstriction
- 刊名：European Journal of Pharmacology
- 出版年：2013
- 出版时间：15 January, 2013
- 年：2013
- 卷：699
- 期：1-3
- 页码：172-179
- 全文大小：315 K
文摘
The effects of a novel adenosine A3 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¡ä-N-methyl-uronamide dihydrochloride] (10?7 M) increased the antigen response up to 61¡À3.0 % and 88¡À5.2 % of maximal contraction, respectively. The agonists of adenosine A1 and A2 adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5¡ä-N-ethylcarboxamidoadenosine], R-PIA [N6-R-phenylisopropyladenosine], and CGS21680 (10?7 M) were ineffective. In vivo intravenous adenosine (600 ¦Ìg/kg) and AB-MECA (30 ¦Ìg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214¡À13.0 % and 220¡À15.2 % , respectively. SSR161421 in vitro (IC50=5.9¡Á10?7 M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED50=0.008 mg/kg) or oral (ED50=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¡Á10?6 M) decreased the AUC of the antigen-induced contraction-time curve to 20.8¡À5.4 % from the 100 % control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC50 values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.