Sanofi Co. Ltd, H-1045 Budapest Tó utca 1-5, Hungary.
Eur J Pharmacol. 2013 Jan 15;699(1-3):172-9. doi: 10.1016/j.ejphar.2012.11.049. Epub 2012 Dec 5.
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.
我们考察了一种新型的腺苷 A(3)受体拮抗剂 SSR161421 对已致敏豚鼠自身抗原和腺苷受体激动剂增强的气道反应的影响。腺苷（10(-5)M）和 AB-MECA[N6-(4-氨基苄基)-腺苷-5'-N-甲基-脲二盐酸盐]（10(-7)M）分别将抗原反应增加至最大收缩的 61±3.0%和 88±5.2%。腺苷 A(1)和 A(2)受体的激动剂 NECA[1-(6-氨基-9H-嘌呤-9-基)-1-脱氧-N-乙基-β-D-呋喃核糖尿苷-5'-N-乙基羧酰胺基腺苷]、R-PIA[N(6)-R-苯异丙基腺苷]和 CGS21680（10(-7)M）均无效。体内静脉给予腺苷（600μg/kg）和 AB-MECA（30μg/kg）分别将阈值抗原剂量诱导的支气管收缩增加了 214±13.0%和 220±15.2%。SSR161421 体外（IC(50)=5.9×10(-7)M）抑制了 AB-MECA 增强的抗原诱导的气道平滑肌收缩，并且在体内静脉（ED(50)=0.008mg/kg）或口服（ED(50)=0.03mg/kg）给药后，也抑制了致敏豚鼠的支气管收缩。抗原本身可以在体外引起气管收缩，在体内引起已致敏豚鼠的支气管收缩。SSR161421（3×10(-6)M）将抗原诱导的收缩-时间曲线的 AUC 从 100%对照水平降低至 20.8±5.4%。SSR161421 有效逆转了抗原诱导的支气管收缩、血浆渗漏和细胞募集，其 EC(50)值分别为 0.33mg/kg 口服、0.02mg/kg 腹腔内和 3mg/kg 腹腔内。
