Abstract
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 [35S]-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.
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Acknowledgments
These studies were supported by the National Science and Technology Major Projects “Major New Drugs Innovation and Development” (2009ZX09103-021) and Beijing Municipal Science & Technology Commission “Z121102002512046”.
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Min Lu and Bo Wang designed the study and wrote the article. W.Z.L., H.S.W. and C.Z. synthesized PQ-69. X.M.Z. and M.Y. performed acquisition analysis and interpretation of pharmacokinetic data. R.B.S. and J.L. initiated the research project.
Min Lu and Bo Wang contributed equally to this work.
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Lu, M., Wang, B., Zhang, C. et al. PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity. Purinergic Signalling 10, 619–629 (2014). https://doi.org/10.1007/s11302-014-9424-5
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DOI: https://doi.org/10.1007/s11302-014-9424-5