Lu Min, Wang Bo, Zhang Cheng, Zhuang Xiaomei, Yuan Mei, Wang Haoshan, Li Weizhang, Su Ruibin, Li Jin
Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, 100850, China.
Purinergic Signal. 2014 Dec;10(4):619-29. doi: 10.1007/s11302-014-9424-5. Epub 2014 Sep 24.
Potent and selective adenosine A1 receptor (A1AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA1 receptor, which was 217-fold more selective compared with hA2A receptors and >1,000-fold selectivity for hA1 over hA3 receptor. The results obtained from [(35)S]-GTPγS binding and cAMP concentration assays indicated that PQ-69 might be an A1AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A1AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A1AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A1AR function, and it could be developed as a potential therapeutic agent.
具有良好药代动力学性质的强效选择性腺苷A1受体（A1AR）拮抗剂有望用作新型利尿剂和抗高血压药。因此，我们设计并合成了一系列新型的4-烷基氨基取代-2-芳基吡唑并[4,3-c]喹啉-3-酮衍生物。本研究的目的是表征优化化合物PQ-69的生物学特性。体外结合试验显示，PQ-69在克隆的hA1受体中的Ki值为0.96 nM，与hA2A受体相比选择性高217倍，对hA1受体的选择性比对hA3受体高1000倍以上。[(35)S]-GTPγS结合试验和cAMP浓度试验结果表明，PQ-69可能是一种具有反向激动剂活性的A1AR拮抗剂。此外，PQ-69对由A1AR激动剂2-氯-N6-环戊基腺苷诱导的离体豚鼠收缩表现出高度抑制活性（pA2值为8.99）。对正常大鼠全身给药PQ-69（0.03、0.3、3 mg/kg）可增加尿流量和钠排泄。此外，与1,3-二丙基-8-环戊基黄嘌呤相比，PQ-69在体外表现出更好的代谢稳定性，在体内具有更长的末端消除半衰期（t1/2）。这些发现表明，PQ-69在体外、离体和体内均对A1AR表现出强效拮抗作用，它可能是研究A1AR功能的有用研究工具，并且可以开发成为一种潜在的治疗药物。
